48 results on '"Paterson IC"'
Search Results
2. Functional Implications of Epstein-Barr Virus Lytic Genes in Carcinogenesis.
- Author
-
Yap LF, Wong AKC, Paterson IC, and Young LS
- Abstract
Epstein-Barr virus (EBV) is associated with a diverse range of tumors of both lymphoid and epithelial origin. Similar to other herpesviruses, EBV displays a bipartite life cycle consisting of latent and lytic phases. Current dogma indicates that the latent genes are key drivers in the pathogenesis of EBV-associated cancers, while the lytic genes are primarily responsible for viral transmission. In recent years, evidence has emerged to show that the EBV lytic phase also plays an important role in EBV tumorigenesis, and the expression of EBV lytic genes is frequently detected in tumor tissues and cell lines. The advent of next generation sequencing has allowed the comprehensive profiling of EBV gene expression, and this has revealed the consistent expression of several lytic genes across various types of EBV-associated cancers. In this review, we provide an overview of the functional implications of EBV lytic gene expression to the oncogenic process and discuss possible avenues for future investigations.
- Published
- 2022
- Full Text
- View/download PDF
3. Author Correction: Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape.
- Author
-
Bruce JP, To KF, Lui VWY, Chung GTY, Chan YY, Tsang CM, Yip KY, Ma BBY, Woo JKS, Hui EP, Mak MKF, Lee SD, Chow C, Velapasamy S, Or YYY, Siu PK, El Ghamrasni S, Prokopec S, Wu M, Kwan JSH, Liu Y, Chan JYK, van Hasselt CA, Young LS, Dawson CW, Paterson IC, Yap LF, Tsao SW, Liu FF, Chan ATC, Pugh TJ, and Lo KW
- Published
- 2022
- Full Text
- View/download PDF
4. Author Correction: Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-β1.
- Author
-
Tan ML, Parkinson EK, Yap LF, and Paterson IC
- Published
- 2022
- Full Text
- View/download PDF
5. A collective statement in support of saving pangolins.
- Author
-
Choo SW, Chong JL, Gaubert P, Hughes AC, O'Brien S, Chaber AL, Antunes A, Platto S, Sun NC, Yu L, Koepfli KP, Suwal TL, Thakur M, Ntie S, Panjang E, Kumaran JV, Mahmood T, Heighton SP, Dorji D, Gonedelé BS, Nelson BR, Djagoun CAMS, Loh IH, Kaspal P, Pauklin S, Michelena T, Zhu H, Lipovich L, Tian X, Deng S, Mason CE, Hu J, White R, Jakubovics NS, Wee WY, Tan TK, Wong KT, Paterson S, Chen M, Zhang Y, Othman RY, Brown LC, Shen B, Shui G, Ang MY, Zhao Y, Li Y, Zhang B, Chong CT, Meng Y, Wong A, Su J, Omar H, Shen H, Tan CH, Xu H, Paterson IC, Wang M, Chan CK, Zhang S, Dutta A, Tee TS, Juvigny-Khenafou NPD, Mutha NVR, and Aziz MA
- Subjects
- Animals, Pangolins
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2022
- Full Text
- View/download PDF
6. HOPX: A Unique Homeodomain Protein in Development and Tumor Suppression.
- Author
-
Caspa Gokulan R, Yap LF, and Paterson IC
- Abstract
Homeobox genes are master regulators of morphogenesis and differentiation by acting at the top of genetic hierarchies and their deregulation is associated with a variety of human diseases. They usually contain a highly conserved sequence that codes for the homeodomain of the protein, a specialized motif with three α helices and an N-terminal arm that aids in DNA binding. However, one homeodomain protein, HOPX, is unique among its family members in that it lacks the capacity to bind DNA and instead functions by interacting with transcriptional regulators. HOPX plays crucial roles in organogenesis and is expressed in both embryonic and adult stem cells. Loss of HOPX expression is common in cancer, where it functions primarily as a tumor suppressor gene. In this review, we describe the function of HOPX in development and discuss its role in carcinogenesis.
- Published
- 2022
- Full Text
- View/download PDF
7. The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates.
- Author
-
Li Y, Ouyang Y, Wu H, Wang P, Huang Y, Li X, Chen H, Sun Y, Hu X, Wang X, Li G, Lu Y, Li C, Lu X, Pang J, Nie T, Sang X, Dong L, Dong W, Jiang J, Paterson IC, Yang X, Hong W, Wang H, and You X
- Subjects
- Acinetobacter baumannii drug effects, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Dose-Response Relationship, Drug, Enterobacteriaceae drug effects, Folic Acid Antagonists chemical synthesis, Folic Acid Antagonists chemistry, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Vancomycin-Resistant Enterococci drug effects, Anti-Bacterial Agents pharmacology, Drug Discovery, Folic Acid metabolism, Folic Acid Antagonists pharmacology
- Abstract
The shortage of new antibiotics makes infections caused by gram-negative (G
- ) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G- strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 μg/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
8. Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance.
- Author
-
Zainal Abidin SAI, Paterson IC, Hunt S, Lambert DW, Higginbotham S, and Pink RC
- Subjects
- Actins metabolism, Cell Transdifferentiation drug effects, Cells, Cultured, Collagen metabolism, Extracellular Vesicles drug effects, Gene Expression Profiling, Humans, MicroRNAs genetics, Myofibroblasts drug effects, Myofibroblasts metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction physiology, Transforming Growth Factor beta1 pharmacology, Cell Transdifferentiation physiology, Extracellular Vesicles metabolism, MicroRNAs metabolism, Myofibroblasts cytology
- Abstract
Transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic tumour-derived factor promotes fibroblast differentiation in the tumour microenvironment and is thought to contribute to the development of pro-tumourigenic cancer-associated fibroblasts (CAFs) by promoting myofibroblast differentiation. miRNA dysregulation has been demonstrated in myofibroblast transdifferentiation and CAF activation, however, their expression varies among cell types and with the method of fibroblast induction. Here, the expression profile of miRNA in human primary oral fibroblasts treated with TGF-β1, to derive a myofibroblastic, CAF-like phenotype, was determined compared to untreated fibroblasts. Myofibroblast transdifferentiation was determined by the expression of alpha-smooth muscle actin (α-SMA) and fibronectin-1 extra domain A (FN-EDA1) using quantitative real-time PCR (qRT-PCR) and western blot. The formation of stress fibres was assessed by fluorescence microscopy, and associated changes in contractility were assessed using collagen contraction assays. Extracellular vesicles (EVs) were purified by using size exclusion chromatography and ultracentrifugation and their size and concentration were determined by nanoparticle tracking analysis. miRNA expression profiling in oral fibroblasts treated with TGF-β1 and their extracellular vesicles was carried out using tiling low-density array cards. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform functional and pathway enrichment analysis of target genes. In this study, TGF-β1 induced a myofibroblastic phenotype in normal oral fibroblasts as assessed by expression of molecular markers, the formation of stress fibres and increased contractility. TaqMan Low-Density Array (TLDA) analysis demonstrated that miR-503 and miR-708 were significantly upregulated, while miR-1276 was significantly downregulated in TGF-β1-treated oral fibroblasts (henceforth termed experimentally-derived CAF, eCAF). The gene functional enrichment analysis showed that the candidate miRNAs have the potential to modulate various pathways; including the Ras associated protein 1 (Rap1), PI3K-Akt, and tumour necrosis factor (TNF) signalling pathways. In addition, altered levels of several miRNAs were detected in eCAF EV, including miR-142 and miR-222. No differences in size or abundance of EV were detected between eCAF and normal oral fibroblast (NOF). Little overlap was observed between changes in cellular and EV miRNA profiles, suggesting the possibility of selective loading of EV miRNA. The study reveals miRNA expression signature could be involved in myofibroblast transdifferentiation and the miRNA cargo of their EV, providing novel insight into the involvement of miRNA in CAF development and function., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
- Full Text
- View/download PDF
9. Extracellular ATP Induced S-Phase Cell Cycle Arrest via P2Y Receptor-Activated ERK Signaling in Poorly Differentiated Oral Squamous Cell Carcinoma SAS Cells.
- Author
-
Lau CC, Aminuddin A, Chan KM, Paterson IC, Law LM, and Ng PY
- Abstract
Extracellular ATP in the tumor microenvironment exhibits either pro- or antitumor effect via interaction with P2Y receptors, but the intracellular signaling and functional roles of P2Y receptors in oral squamous cell carcinoma (OSCC) are unclear. We aimed to study the effect of ATP on OSCC cell lines and the potential mechanisms involved. Through GEPIA dataset analysis, high expression levels of mRNA encoding P2Y receptors, the ATP-induced G protein-coupled receptors, were associated with better overall patient survival in head and neck squamous cell carcinoma. qPCR analysis showed that the poorly differentiated OSCC SAS cell line, had higher P2RY1 expression level compared to the well-differentiated H103 and H376 cell lines. Western blotting and flow cytometry analyses revealed that ATP phosphorylated ERK and elevated intracellular calcium signaling in all tested cell lines. A significant S-phase cell cycle arrest was observed in SAS, and preincubation with the MEK inhibitor PD0325901 reversed the ATP-induced S-phase arrest. We further demonstrated that ATP induced a slight reduction in cell count and colony formation yet significant apoptosis in SAS. Overall, we postulate that the ATP-induced S-phase arrest effect in SAS cells may be regulated through P2Y receptor-mediated ERK signaling, thus suggesting a potential antitumor effect of ATP via interaction with its distinct profile of P2Y receptors.
- Published
- 2021
- Full Text
- View/download PDF
10. Establishing a technique for isolation and characterization of human periodontal ligament derived mesenchymal stem cells.
- Author
-
Banavar SR, Rawal SY, Paterson IC, Singh G, Davamani F, Khoo SP, and Tan EL
- Abstract
Mesenchymal stem cells (MSCs) are extensively used in tissue regenerative procedures. One source of MSCs is the periodontal ligament (PDL) of teeth. Isolation of MSCs from extracted teeth is reasonably simple, being less invasive and presenting fewer ethical concerns than does the harvesting of MSC's from other sites. The objectives of this study were to isolate and characterize the PDL stem cells (PDLSC) from healthy adults' extracted teeth and then to characterize them by comparing them with bone-marrow derived MSCs (BMMSC)., Methods: The PDL tissue was scraped from the roots of freshly extracted teeth to enzymatically digest using collagenase. The cells were sub-cultured. Flow-cytometric analysis for the MSC surface-markers CD105, CD73, CD166, CD90, CD34, CD45 and HLA-DR was performed. To confirm the phenotype, total RNA was extracted to synthesize cDNA and which was then subjected to RT-PCR. The gene-expression for Oct4A, Sox2, NANOG and GAPDH was determined by gel-electrophoresis. To assess their multilineage potential, cells were cultured with osteogenic, chondrogenic and adipogenic medium and then stained by Alizarin-red, Alcian-blue and Oil-Red-O respectively. MSCs from the bone-marrow were processed similarly to serve as controls., Results: The cells isolated from extracted teeth expanded successfully. On flow-cytometric analysis, the cells were positive for CD73, CD90, CD105, CD166 and negative for CD34, CD45 and HLA-DR. The PDLSCs expressed Oct4A, Sox2, and NANOG mRNA with GAPDH expression. Cells cultured in the osteogenic, chondrogenic and adipogenic media stained positive for Alizarin-red, Alcian-blue and Oil- Red-O respectively. The surface marker expression and the trilineage differentiation characteristics were comparable to those of the BMMSCs., Conclusions: The periodontal ligament tissue of extracted teeth is a potential source of therapeutically useful MSCs. Harvesting them is not invasive and are a promising source of MSC as the PDLSCs showed characteristics similar to those of the highly regarded MSC's derived from bone-marrow., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)
- Published
- 2021
- Full Text
- View/download PDF
11. Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape.
- Author
-
Bruce JP, To KF, Lui VWY, Chung GTY, Chan YY, Tsang CM, Yip KY, Ma BBY, Woo JKS, Hui EP, Mak MKF, Lee SD, Chow C, Velapasamy S, Or YYY, Siu PK, El Ghamrasni S, Prokopec S, Wu M, Kwan JSH, Liu Y, Chan JYK, van Hasselt CA, Young LS, Dawson CW, Paterson IC, Yap LF, Tsao SW, Liu FF, Chan ATC, Pugh TJ, and Lo KW
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Carcinogenesis drug effects, Carcinogenesis genetics, Carcinogenesis immunology, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections therapy, Epstein-Barr Virus Infections virology, Female, Gene Expression Regulation, Viral immunology, Herpesvirus 4, Human immunology, Herpesvirus 4, Human pathogenicity, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Methionine Adenosyltransferase antagonists & inhibitors, Methionine Adenosyltransferase metabolism, Mice, NF-kappa B metabolism, Nasopharyngeal Carcinoma genetics, Nasopharyngeal Carcinoma therapy, Nasopharyngeal Carcinoma virology, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms therapy, Nasopharyngeal Neoplasms virology, Nasopharynx immunology, Nasopharynx pathology, Nasopharynx surgery, Nasopharynx virology, Receptor, Transforming Growth Factor-beta Type II genetics, Receptor, Transforming Growth Factor-beta Type II metabolism, Sequence Deletion, Signal Transduction drug effects, Signal Transduction genetics, Signal Transduction immunology, Tumor Escape drug effects, Whole Genome Sequencing, Xenograft Model Antitumor Assays, Epstein-Barr Virus Infections immunology, Herpesvirus 4, Human genetics, Nasopharyngeal Carcinoma immunology, Nasopharyngeal Neoplasms immunology, Tumor Escape genetics
- Abstract
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
- Published
- 2021
- Full Text
- View/download PDF
12. 3D Clumps/Extracellular Matrix Complexes of Periodontal Ligament Stem Cells Ameliorate the Attenuating Effects of LPS on Proliferation and Osteogenic Potential.
- Author
-
Banavar SR, Rawal SY, Pulikkotil SJ, Daood U, Paterson IC, Davamani FA, Kajiya M, Kurihara H, Khoo SP, and Tan EL
- Abstract
Background: The effects of lipopolysaccharide (LPS) on cell proliferation and osteogenic potential (OP) of MSCs have been frequently studied., Objective: to compare the effects of LPS on periodontal-ligament-derived mesenchymal stem cells (PDLSCs) in monolayer and 3D culture., Methods: The PDLSCs were colorimetrically assessed for proliferation and osteogenic potential (OP) after LPS treatment. The 3D cells were manually prepared by scratching and allowing them to clump up. The clumps (C-MSCs) were treated with LPS and assessed for Adenosine triphosphate (ATP) and OP. Raman spectroscopy was used to analyze calcium salts, DNA, and proline/hydroxyproline. Multiplexed ELISA was performed to assess LPS induced local inflammation., Results: The proliferation of PDLSCs decreased with LPS. On Day 28, LPS-treated cells showed a reduction in their OP. C-MSCs with LPS did not show a decrease in ATP production. Principal bands identified in Raman analysis were the P-O bond at 960 cm
-1 of the mineral component, 785 cm-1 , and 855 cm-1 showing qualitative changes in OP, proliferation, and proline/hydroxyproline content, respectively. ELISA confirmed increased levels of IL-6 and IL-8 but with the absence of TNF-α and IL-1β secretion., Conclusions: These observations demonstrate that C-MSCs are more resistant to the effects of LPS than cells in monolayer cell culture. Though LPS stimulation of C-MSCs creates an early pro-inflammatory milieu by secreting IL-6 and IL-8, PDLSCs possess inactivated TNF promoter and an ineffective caspase-1 activating process.- Published
- 2021
- Full Text
- View/download PDF
13. Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-β1.
- Author
-
Tan ML, Parkinson EK, Yap LF, and Paterson IC
- Subjects
- Cell Differentiation genetics, Cell Movement drug effects, Cell Movement genetics, Cellular Senescence drug effects, Humans, Myofibroblasts pathology, Neoplasm Invasiveness genetics, Pyridines pharmacology, Pyrimidinones pharmacology, Autophagy drug effects, Autophagy genetics, Autophagy physiology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cellular Senescence genetics, Fibroblasts pathology, Fibroblasts physiology, Mouth Neoplasms genetics, Mouth Neoplasms pathology, Transforming Growth Factor beta1 physiology
- Abstract
Many of the characteristics ascribed to cancer-associated fibroblasts (CAFs) are shared by activated, autophagic and senescent fibroblasts. Whilst most oral squamous cell carcinomas (OSCCs) are genetically unstable (GU-OSCC), genetically stable variants (GS-OSCC) have been described and, notably, CAF activation (myofibroblast differentiation) and senescence are characteristics particularly associated with GU-OSCCs. However, it is not known whether autophagy is disrupted in these cells or whether autophagy regulates the development of the myofibroblast and senescent phenotypes. In this study, we show that senescent CAFs from GU-OSCCs contained more autophagosomes than normal human oral fibroblasts (NHOFs) and CAFs from GS-OSCCs possibly due to autophagic impairment. Further, we show that deregulation of autophagy in normal fibroblasts, either by inhibition with autophagy inhibitor, SAR405, or activation with TGF-β1, induced fibroblast activation and senescence: In response to TGF-β1, autophagy was induced prior to the development of the activated and senescent phenotypes. Lastly, we show that both SAR405- and TGF-β1-treated NHOFs enhance OSCC cell migration but only TGF-β1-treated cells increase OSCC invasion through Matrigel, indicating that TGF-β1 has additional effects that are independent of fibroblast activation/senescence. These results suggest a functional role for autophagy in the development of myofibroblast and CAF phenotypes.
- Published
- 2021
- Full Text
- View/download PDF
14. Deregulation of lysophosphatidic acid metabolism in oral cancer promotes cell migration via the up-regulation of COX-2.
- Author
-
Abdul Rahman M, Tan ML, Johnson SP, Hollows RJ, Chai WL, Mansell JP, Yap LF, and Paterson IC
- Abstract
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease., Competing Interests: The authors declare there are no competing interests., (©2020 Abdul Rahman et al.)
- Published
- 2020
- Full Text
- View/download PDF
15. Profiling lysophosphatidic acid levels in plasma from head and neck cancer patients.
- Author
-
Abdul Rahman M, Mohamad Haron DE, Hollows RJ, Abdul Ghani ZDF, Ali Mohd M, Chai WL, Ng CC, Lye MS, Karsani SA, Yap LF, and Paterson IC
- Abstract
Head and neck squamous cell carcinoma (HNSCC) represents a significant world health problem, with approximately 600,000 new cases being diagnosed annually. The prognosis for patients with HNSCC is poor and, therefore, the identification of biomarkers for screening, diagnosis and prognostication would be clinically beneficial. A limited number of studies have used lipidomics to profile lipid species in the plasma of cancer patients. However, the profile and levels of lysophosphatidic acid (LPA) species have not been examined in HNSCC. In this study, a targeted lipidomics approach using liquid chromatography triple quadrupole mass spectrometry (LCMS/MS) was used to analyse the concentration of LPA (16:0 LPA, 18:0 LPA, 18:1 LPA, 18:2 LPA and 20:4 LPA) in the plasma of patients with oral squamous cell carcinoma (OSCC) and nasopharyngeal carcinoma (NPC), together with healthy controls. The levels of three LPA species (18:1 LPA, 18:2 LPA and 20:4 LPA) were significantly lower in the plasma of OSCC patients, whilst the concentrations of all five LPA species tested were significantly lower in plasma from NPC patients. Furthermore, the order of abundance of LPA species in plasma was different between the control and cancer groups, with 16:0 LPA, 18:0 LPA levels being more abundant in OSCC and NPC patients. Medium to strong correlations were observed using all pairs of LPA species and a clear separation of the normal and tumour groups was observed using PCA analysis. In summary, the results of this study showed that the levels of several LPA species in the plasma of patients with OSCC and NPC were lower than those from healthy individuals. Understanding these variations may provide novel insights into the role of LPA in these cancers., Competing Interests: The authors declare there are no competing interests., (©2020 Abdul Rahman et al.)
- Published
- 2020
- Full Text
- View/download PDF
16. Monoamine oxidase A is down-regulated in EBV-associated nasopharyngeal carcinoma.
- Author
-
Lee HM, Sia APE, Li L, Sathasivam HP, Chan MSA, Rajadurai P, Tsang CM, Tsao SW, Murray PG, Tao Q, Paterson IC, and Yap LF
- Subjects
- Cell Line, Tumor, Down-Regulation, Epigenesis, Genetic, Epithelial Cells metabolism, Herpesvirus 4, Human pathogenicity, Humans, Interleukin-6 metabolism, Monoamine Oxidase metabolism, Nasopharyngeal Carcinoma genetics, Nasopharyngeal Neoplasms genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Monoamine Oxidase genetics, Nasopharyngeal Carcinoma metabolism, Nasopharyngeal Neoplasms metabolism
- Abstract
Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.
- Published
- 2020
- Full Text
- View/download PDF
17. Development of small molecule inhibitors targeting TGF-β ligand and receptor: Structures, mechanism, preclinical studies and clinical usage.
- Author
-
Wang H, Chen M, Sang X, You X, Wang Y, Paterson IC, Hong W, and Yang X
- Subjects
- Animals, Humans, Ligands, Molecular Structure, Pyrazoles chemical synthesis, Pyrazoles chemistry, Receptors, Transforming Growth Factor beta metabolism, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Transforming Growth Factor beta metabolism, Drug Development, Pyrazoles pharmacology, Receptors, Transforming Growth Factor beta antagonists & inhibitors, Small Molecule Libraries pharmacology, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and differentiation. Following binding to type I and II TGF-β serine/threonine kinase receptors, TGF-β activates downstream signaling cascades involving both SMAD-dependent and -independent pathways. Aberrant TGF-β signaling is associated with a variety of diseases, such as fibrosis, cardiovascular disease and cancer. Hence, the TGF-β signaling pathway is recognized as a potential drug target. Various organic molecules have been designed and developed as TGF-β signaling pathway inhibitors and they function by either down-regulating the expression of TGF-β or by inhibiting the kinase activities of the TGF-β receptors. In this review, we discuss the current status of research regarding organic molecules as TGF-β inhibitors, focusing on the biological functions and the binding poses of compounds that are in the market or in the clinical or pre-clinical phases of development., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
18. The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions.
- Author
-
Wu H, Sun Y, Wong WL, Cui J, Li J, You X, Yap LF, Huang Y, Hong W, Yang X, Paterson IC, and Wang H
- Subjects
- A549 Cells, Benzylamines chemical synthesis, Cell Movement drug effects, Drug Design, Epithelial-Mesenchymal Transition drug effects, Humans, Ligands, Molecular Docking Simulation, Signal Transduction drug effects, Benzylamines pharmacology, Protein Binding drug effects, Receptors, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
19. Collagen Induces a More Proliferative, Migratory and Chemoresistant Phenotype in Head and Neck Cancer via DDR1.
- Author
-
Lai SL, Tan ML, Hollows RJ, Robinson M, Ibrahim M, Margielewska S, Parkinson EK, Ramanathan A, Zain RB, Mehanna H, Spruce RJ, Wei W, Chung I, Murray PG, Yap LF, and Paterson IC
- Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, and showed that it is over-expressed in HNSCC tissues. Further, we demonstrated that collagen promoted the proliferation and migration of HNSCC cells and attenuated the apoptotic response to cisplatin. Knockdown of DDR1 in HNSCC cells demonstrated that these tumour-promoting effects of collagen are mediated by DDR1. Our data suggest that specific inhibitors of DDR1 might provide novel therapeutic opportunities to treat HNSCC.
- Published
- 2019
- Full Text
- View/download PDF
20. Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles.
- Author
-
Khoo XH, Paterson IC, Goh BH, and Lee WL
- Abstract
Drug resistance remains a severe problem in most chemotherapy regimes. Recently, it has been suggested that cancer cell-derived extracellular vesicles (EVs) could mediate drug resistance. In this study, the role of EVs in mediating the response of oral squamous cell carcinoma (OSCC) cells to cisplatin was investigated. We isolated and characterized EVs from OSCC cell lines showing differential sensitivities to cisplatin. Increased EV production was observed in both de novo (H314) and adaptive (H103/cisD2) resistant lines compared to sensitive H103 cells. The protein profiles of these EVs were then analyzed. Differences in the proteome of EVs secreted by H103 and H103/cisD2 indicated that adaptation to cisplatin treatment caused significant changes in the secreted nanovesicles. Intriguingly, both resistant H103/cisD2 and H314 cells shared a highly similar EV protein profile including downregulation of the metal ion transporter, ATP1B3, in the EVs implicating altered drug delivery. ICP-MS analysis revealed that less cisplatin accumulated in the resistant cells, but higher levels were detected in their EVs. Therefore, we inhibited EV secretion from the cells using a proton pump inhibitor and observed an increased drug sensitivity in cisplatin-resistant H314 cells. This finding suggests that control of EV secretion could be a potential strategy to enhance the efficacy of cancer treatment.
- Published
- 2019
- Full Text
- View/download PDF
21. Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and modular analysis of their protein-coding gene association networks.
- Author
-
Walters K, Sarsenov R, Too WS, Hare RK, Paterson IC, Lambert DW, Brown S, and Bradford JR
- Subjects
- Computational Biology, Gene Expression Profiling, Genetic Association Studies, Humans, Neoplasms pathology, Tumor Microenvironment, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Neoplasms genetics, RNA, Long Noncoding genetics, RNA, Messenger genetics
- Abstract
Background: Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes in diseases such as cancer, although the functions of most remain poorly understood. To address this, here we apply a novel strategy to integrate gene expression profiles across 32 cancer types, and cluster human lncRNAs based on their pan-cancer protein-coding gene associations. By doing so, we derive 16 lncRNA modules whose unique properties allow simultaneous inference of function, disease specificity and regulation for over 800 lncRNAs., Results: Remarkably, modules could be grouped into just four functional themes: transcription regulation, immunological, extracellular, and neurological, with module generation frequently driven by lncRNA tissue specificity. Notably, three modules associated with the extracellular matrix represented potential networks of lncRNAs regulating key events in tumour progression. These included a tumour-specific signature of 33 lncRNAs that may play a role in inducing epithelial-mesenchymal transition through modulation of TGFβ signalling, and two stromal-specific modules comprising 26 lncRNAs linked to a tumour suppressive microenvironment and 12 lncRNAs related to cancer-associated fibroblasts. One member of the 12-lncRNA signature was experimentally supported by siRNA knockdown, which resulted in attenuated differentiation of quiescent fibroblasts to a cancer-associated phenotype., Conclusions: Overall, the study provides a unique pan-cancer perspective on the lncRNA functional landscape, acting as a global source of novel hypotheses on lncRNA contribution to tumour progression.
- Published
- 2019
- Full Text
- View/download PDF
22. In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5-HT 2 and α 1 receptors.
- Author
-
Heng HL, Chee CF, Thy CK, Tee JT, Chin SP, Herr DR, Buckle MJC, Paterson IC, Doughty SW, Abd Rahman N, and Chung LY
- Subjects
- Adrenergic alpha-1 Receptor Agonists chemistry, Adrenergic alpha-1 Receptor Agonists metabolism, Aporphines metabolism, Binding Sites, HEK293 Cells, Humans, Kinetics, Molecular Docking Simulation, Protein Structure, Tertiary, Receptor, Serotonin, 5-HT2A chemistry, Receptor, Serotonin, 5-HT2A genetics, Receptors, Adrenergic, alpha-1 chemistry, Receptors, Adrenergic, alpha-1 genetics, Serotonin metabolism, Serotonin 5-HT2 Receptor Agonists chemistry, Serotonin 5-HT2 Receptor Agonists metabolism, Stereoisomerism, Structure-Activity Relationship, Aporphines chemistry, Receptor, Serotonin, 5-HT2A metabolism, Receptors, Adrenergic, alpha-1 metabolism, Serotonin chemistry
- Abstract
Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT
2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb = 8.14 at the 5-HT2C receptor). Both (R)- and (S)-glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5-HT2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT2A receptor., (© 2018 John Wiley & Sons A/S.)- Published
- 2019
- Full Text
- View/download PDF
23. OSC1: Assessment of Cytotoxicity of Microcrystalline Cellulose Reinforced Denture Base Resin.
- Author
-
Rahaman Ali AAA, May LW, Paterson IC, and John J
- Published
- 2018
- Full Text
- View/download PDF
24. Corrigendum: A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
- Author
-
Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, Hunt S, Catto JWF, Coletta RD, Mellone M, Thomas GJ, Parkinson EK, Prime SS, Paterson IC, Buttle DJ, and Lambert DW
- Published
- 2018
- Full Text
- View/download PDF
25. The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers.
- Author
-
Velapasamy S, Dawson CW, Young LS, Paterson IC, and Yap LF
- Abstract
The transforming growth factor-β (TGF-β) signalling pathway plays a critical role in carcinogenesis. It has a biphasic action by initially suppressing tumorigenesis but promoting tumour progression in the later stages of disease. Consequently, the functional outcome of TGF-β signalling is strongly context-dependent and is influenced by various factors including cell, tissue and cancer type. Disruption of this pathway can be caused by various means, including genetic and environmental factors. A number of human viruses have been shown to modulate TGF-β signalling during tumorigenesis. In this review, we describe how this pathway is perturbed in Epstein-Barr virus (EBV)-associated cancers and how EBV interferes with TGF-β signal transduction. The role of TGF-β in regulating the EBV life cycle in tumour cells is also discussed.
- Published
- 2018
- Full Text
- View/download PDF
26. Clinico-pathological features of oropharyngeal squamous cell carcinomas in Malaysia with reference to HPV infection.
- Author
-
Yap LF, Lai SL, Rhodes A, Sathasivam HP, Abdullah MA, Pua KC, Rajadurai P, Cheah PL, Thavaraj S, Robinson M, and Paterson IC
- Abstract
Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising in Western countries and this has been attributed to human papillomavirus (HPV) infection. p16 expression is a marker for HPV infection and p16 positive OPSCC is now recognized as a separate disease entity. There are only limited data available regarding HPV-related OPSCC in Asian countries and no data from Malaysia., Methods: We identified 60 Malaysian patients with OPSCC over a 12-year period (2004-2015) from four different hospitals in two major cities, Kuala Lumpur and Penang. The detection of HPV was carried out using p16 immunohistochemistry and high risk HPV DNA in situ hybridisation., Results: Overall, 15 (25%) tumours were p16 positive by immunohistochemistry, 10 of which were also positive for high risk HPV DNA by in situ hybridisation. By comparison, a matched cohort of UK patients had a p16 positive rate of 49%. However, between 2009 and 2015, where cases were available from all four hospitals, 13 of 37 (35%) cases were p16 positive. In our Malaysian cohort, 53% of patients were of Chinese ethnicity and 80% of the p16 positive cases were found in these patients; no Indian patients had p16 positive disease, despite representing 35% of the total cohort., Conclusion: The proportion of OPSCCs associated with HPV in Malaysia appears to be lower than in European and American cohorts and could possibly be more prevalent amongst Malaysians of Chinese ethnicity. Further, our data suggests that the burden of HPV-related OPSCC could be increasing in Malaysia. Larger cross-sectional studies of Malaysian patients are required to determine the public health implications of these preliminary findings., Competing Interests: This study had ethical approval from the relevant institutional medical research and ethics boards (Reference Numbers: NMRR-12-13,577; UMMC 20164–2341; SDMC 201211.3; 11/NE/0118).The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Published
- 2018
- Full Text
- View/download PDF
27. A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
- Author
-
Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, Hunt S, Catto JWF, Coletta RD, Mellone M, Thomas GJ, Parkinson EK, Prime SS, Paterson IC, Buttle DJ, and Lambert DW
- Subjects
- Cell Differentiation physiology, Cell Line, Tumor, Humans, Myofibroblasts metabolism, Phenotype, Signal Transduction physiology, Tumor Microenvironment physiology, Cancer-Associated Fibroblasts metabolism, MicroRNAs metabolism, Mouth Neoplasms metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
- Published
- 2018
- Full Text
- View/download PDF
28. Correction: Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT 2 and α 1 receptor antagonists.
- Author
-
Heng HL, Chee CF, Chin SP, Ouyang Y, Wang H, Buckle MJC, Herr DR, Paterson IC, Doughty SW, Abd Rahman N, and Chung LY
- Abstract
[This corrects the article DOI: 10.1039/C7MD00629B.].
- Published
- 2018
- Full Text
- View/download PDF
29. Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT 2 and α 1 receptor antagonists.
- Author
-
Heng HL, Chee CF, Chin SP, Ouyang Y, Wang H, Buckle MJC, Herr DR, Paterson IC, Doughty SW, Abd Rahman N, and Chung LY
- Abstract
In this study, the ( S )-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT
2 and adrenergic α1 receptor subtypes using a transforming growth factor-α shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT2 and α1 receptors. ( R )-roemerine was the most potent compound at 5-HT2A and 5-HT2C receptors (p Kb = 7.8-7.9) with good selectivity compared to ( S )-roemerine at these two receptors and compared to its activity at 5-HT2B , α1A , α1B and α1D receptors.- Published
- 2018
- Full Text
- View/download PDF
30. Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens.
- Author
-
Hong W, Li J, Chang Z, Tan X, Yang H, Ouyang Y, Yang Y, Kaur S, Paterson IC, Ngeow YF, and Wang H
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Drug Design, Drug Resistance, Multiple, Bacterial, Indoles chemical synthesis, Indoles chemistry, Models, Molecular, Anti-Bacterial Agents pharmacology, Gram-Negative Bacteria drug effects, Gram-Positive Bacteria drug effects, Indoles pharmacology
- Abstract
The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.
- Published
- 2017
- Full Text
- View/download PDF
31. Distinct Biological Potential of Streptococcus gordonii and Streptococcus sanguinis Revealed by Comparative Genome Analysis.
- Author
-
Zheng W, Tan MF, Old LA, Paterson IC, Jakubovics NS, and Choo SW
- Subjects
- Base Composition, Comparative Genomic Hybridization, Computational Biology methods, Genome Size, Molecular Sequence Annotation, Phylogeny, Prophages genetics, Streptococcus gordonii virology, Streptococcus sanguis virology, Virulence, Virulence Factors genetics, Genome, Bacterial, Genomics methods, Streptococcal Infections microbiology, Streptococcus gordonii physiology, Streptococcus sanguis physiology
- Abstract
Streptococcus gordonii and Streptococcus sanguinis are pioneer colonizers of dental plaque and important agents of bacterial infective endocarditis (IE). To gain a greater understanding of these two closely related species, we performed comparative analyses on 14 new S. gordonii and 5 S. sanguinis strains using various bioinformatics approaches. We revealed S. gordonii and S. sanguinis harbor open pan-genomes and share generally high sequence homology and number of core genes including virulence genes. However, we observed subtle differences in genomic islands and prophages between the species. Comparative pathogenomics analysis identified S. sanguinis strains have genes encoding IgA proteases, mitogenic factor deoxyribonucleases, nickel/cobalt uptake and cobalamin biosynthesis. On the contrary, genomic islands of S. gordonii strains contain additional copies of comCDE quorum-sensing system components involved in genetic competence. Two distinct polysaccharide locus architectures were identified, one of which was exclusively present in S. gordonii strains. The first evidence of genes encoding the CylA and CylB system by the α-haemolytic S. gordonii is presented. This study provides new insights into the genetic distinctions between S. gordonii and S. sanguinis, which yields understanding of tooth surfaces colonization and contributions to dental plaque formation, as well as their potential roles in the pathogenesis of IE.
- Published
- 2017
- Full Text
- View/download PDF
32. Mechanisms of sphingosine 1-phosphate receptor signalling in cancer.
- Author
-
Patmanathan SN, Wang W, Yap LF, Herr DR, and Paterson IC
- Subjects
- Animals, Humans, Neoplasms metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, Lysosphingolipid agonists, Receptors, Lysosphingolipid antagonists & inhibitors, Signal Transduction, Sphingosine metabolism, Lysophospholipids metabolism, Neoplasms pathology, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives
- Abstract
S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P
1-5 . Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. However, cooperativity between the individual S1PRs, functional interactions with receptor tyrosine kinases and the sub-cellular localisation of the S1PRs within tumour cells also appear to play a role in mediating the effects of S1PR signalling during carcinogenesis. Here we review what is known regarding the role of individual S1PRs in cancer and discuss the recent evidence to suggest cross-talk between the S1PRs and other cellular signalling pathways in cancer. We will also discuss the therapeutic potential of targeting the S1PRs and their downstream signalling pathways for the treatment of cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
33. Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3.
- Author
-
Lee HM, Lo KW, Wei W, Tsao SW, Chung GTY, Ibrahim MH, Dawson CW, Murray PG, Paterson IC, and Yap LF
- Subjects
- Adult, Aged, Animals, Carcinoma, Cell Line, Tumor, Cell Movement drug effects, Cell Movement physiology, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections metabolism, Epstein-Barr Virus Infections pathology, Female, Gene Expression Regulation, Neoplastic physiology, Gene Knockdown Techniques, Heterografts, Humans, Lysophospholipids pharmacology, Male, Middle Aged, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms metabolism, Nasopharyngeal Neoplasms pathology, RNA, Messenger genetics, Receptors, Lysosphingolipid genetics, Receptors, Lysosphingolipid physiology, Signal Transduction physiology, Sphingosine pharmacology, Sphingosine physiology, Sphingosine-1-Phosphate Receptors, Up-Regulation, Epstein-Barr Virus Infections complications, Lysophospholipids physiology, Nasopharyngeal Neoplasms virology, Oncogene Protein v-akt metabolism, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives
- Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
34. Susceptibility of Human Oral Squamous Cell Carcinoma (OSCC) H103 and H376 cell lines to Retroviral OSKM mediated reprogramming.
- Author
-
Verusingam ND, Yeap SK, Ky H, Paterson IC, Khoo SP, Cheong SK, Ong AHK, and Kamarul T
- Abstract
Although numbers of cancer cell lines have been shown to be successfully reprogrammed into induced pluripotent stem cells (iPSCs), reprogramming Oral Squamous Cell Carcinoma (OSCC) to pluripotency in relation to its cancer cell type and the expression pattern of pluripotent genes under later passage remain unexplored. In our study, we reprogrammed and characterised H103 and H376 oral squamous carcinoma cells using retroviral OSKM mediated method. Reprogrammed cells were characterized for their embryonic stem cells (ESCs) like morphology, pluripotent gene expression via quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence staining, embryoid bodies (EB) formation and directed differentiation capacity. Reprogrammed H103 (Rep-H103) exhibited similar ESCs morphologies with flatten cells and clear borders on feeder layer. Reprogrammed H376 (Rep-H376) did not show ESCs morphologies but grow with a disorganized morphology. Critical pluripotency genes Oct4, Sox2 and Nanog were expressed higher in Rep-H103 against the parental counterpart from passage 5 to passage 10. As for Rep-H376, Nanog expression against its parental counterpart showed a significant decrease at passage 5 and although increased in passage 10, the level of expression was similar to the parental cells. Rep-H103 exhibited pluripotent signals (Oct4, Sox2, Nanog and Tra-1-60) and could form EB with the presence of three germ layers markers. Rep-H103 displayed differentiation capacity into adipocytes and osteocytes. The OSCC cell line H103 which was able to be reprogrammed into an iPSC like state showed high expression of Oct4, Sox2 and Nanog at late passage and may provide a potential iPSC model to study multi-stage oncogenesis in OSCC., Competing Interests: The authors declare there are no competing interests.
- Published
- 2017
- Full Text
- View/download PDF
35. Fibroblast activation and senescence in oral cancer.
- Author
-
Prime SS, Cirillo N, Hassona Y, Lambert DW, Paterson IC, Mellone M, Thomas GJ, James EN, and Parkinson EK
- Subjects
- Cellular Senescence, Fibroblasts cytology, Fibroblasts metabolism, Humans, Metabolome, Mouth Neoplasms metabolism, Mouth Neoplasms physiopathology, Fibroblasts physiology, Mouth Neoplasms pathology
- Abstract
There is now compelling evidence that the tumour stroma plays an important role in the pathogenesis of cancers of epithelial origin. The pre-eminent cell type of the stroma is carcinoma-associated fibroblasts. These cells demonstrate remarkable heterogeneity with activation and senescence being common stress responses. In this review, we summarise the part that these cells play in cancer, particularly oral cancer, and present evidence to show that activation and senescence reflect a unified programme of fibroblast differentiation. We report advances concerning the senescent fibroblast metabolome, mechanisms of gene regulation in these cells and ways in which epithelial cell adhesion is dysregulated by the fibroblast secretome. We suggest that the identification of fibroblast stress responses may be a valuable diagnostic tool in the determination of tumour behaviour and patient outcome. Further, the fact that stromal fibroblasts are a genetically stable diploid cell population suggests that they may be ideal therapeutic targets and early work in this context is encouraging., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
36. HOPX functions as a tumour suppressor in head and neck cancer.
- Author
-
Yap LF, Lai SL, Patmanathan SN, Gokulan R, Robinson CM, White JB, Chai SJ, Rajadurai P, Prepageran N, Liew YT, Lopes V, Wei W, Hollows RJ, Murray PG, Lambert DW, Hunter KD, and Paterson IC
- Subjects
- Carcinoma, Squamous Cell pathology, Cell Line, Tumor, DNA Damage, DNA Methylation, Down-Regulation, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms pathology, Homeostasis, Humans, Promoter Regions, Genetic, RNA, Messenger genetics, Squamous Cell Carcinoma of Head and Neck, Transcription, Genetic, Carcinoma, Squamous Cell genetics, Genes, Tumor Suppressor, Head and Neck Neoplasms genetics, Homeodomain Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis.
- Published
- 2016
- Full Text
- View/download PDF
37. Comparative Genome Analysis of Fusobacterium nucleatum.
- Author
-
Ang MY, Dutta A, Wee WY, Dymock D, Paterson IC, and Choo SW
- Subjects
- Fusobacterium nucleatum classification, Gene Transfer, Horizontal, Genomic Islands, Phylogeny, Fusobacterium nucleatum genetics, Genome, Bacterial
- Abstract
Fusobacterium nucleatum is considered to be a key oral bacterium in recruiting periodontal pathogens into subgingival dental plaque. Currently F. nucleatum can be subdivided into five subspecies. Our previous genome analysis of F. nucleatum W1481 (referred to hereafter as W1481), isolated from an 8-mm periodontal pocket in a patient with chronic periodontitis, suggested the possibility of a new subspecies. To further investigate the biology and relationships of this possible subspecies with other known subspecies, we performed comparative analysis between W1481 and 35 genome sequences represented by the five known Fusobacterium subspecies. Our analyses suggest that W1481 is most likely a new F. nucleatum subspecies, supported by evidence from phylogenetic analyses and maximal unique match indices (MUMi). Interestingly, we found a horizontally transferred W1481-specific genomic island harboring the tripartite ATP-independent (TRAP)-like transporter genes, suggesting this bacterium might have a high-affinity transport system for the C4-dicarboxylates malate, succinate, and fumarate. Moreover, we found virulence genes in the W1481 genome that may provide a strong defense mechanism which might enable it to colonize and survive within the host by evading immune surveillance. This comparative study provides better understanding of F. nucleatum and the basis for future functional work on this important pathogen., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2016
- Full Text
- View/download PDF
38. Pangolin genomes and the evolution of mammalian scales and immunity.
- Author
-
Choo SW, Rayko M, Tan TK, Hari R, Komissarov A, Wee WY, Yurchenko AA, Kliver S, Tamazian G, Antunes A, Wilson RK, Warren WC, Koepfli KP, Minx P, Krasheninnikova K, Kotze A, Dalton DL, Vermaak E, Paterson IC, Dobrynin P, Sitam FT, Rovie-Ryan JJ, Johnson WE, Yusoff AM, Luo SJ, Karuppannan KV, Fang G, Zheng D, Gerstein MB, Lipovich L, O'Brien SJ, and Wong GJ
- Subjects
- Adaptation, Physiological, Animals, Endangered Species, Interferons genetics, Mammals anatomy & histology, Mammals classification, Mammals immunology, Receptors, Odorant genetics, Animal Scales anatomy & histology, Evolution, Molecular, Genome, Immunity, Innate genetics, Mammals genetics
- Abstract
Pangolins, unique mammals with scales over most of their body, no teeth, poor vision, and an acute olfactory system, comprise the only placental order (Pholidota) without a whole-genome map. To investigate pangolin biology and evolution, we developed genome assemblies of the Malayan (Manis javanica) and Chinese (M. pentadactyla) pangolins. Strikingly, we found that interferon epsilon (IFNE), exclusively expressed in epithelial cells and important in skin and mucosal immunity, is pseudogenized in all African and Asian pangolin species that we examined, perhaps impacting resistance to infection. We propose that scale development was an innovation that provided protection against injuries or stress and reduced pangolin vulnerability to infection. Further evidence of specialized adaptations was evident from positively selected genes involving immunity-related pathways, inflammation, energy storage and metabolism, muscular and nervous systems, and scale/hair development. Olfactory receptor gene families are significantly expanded in pangolins, reflecting their well-developed olfaction system. This study provides insights into mammalian adaptation and functional diversification, new research tools and questions, and perhaps a new natural IFNE-deficient animal model for studying mammalian immunity., (© 2016 Choo et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2016
- Full Text
- View/download PDF
39. PGD: a pangolin genome hub for the research community.
- Author
-
Tan TK, Tan KY, Hari R, Mohamed Yusoff A, Wong GJ, Siow CC, Mutha NV, Rayko M, Komissarov A, Dobrynin P, Krasheninnikova K, Tamazian G, Paterson IC, Warren WC, Johnson WE, O'Brien SJ, and Choo SW
- Subjects
- Animals, Expressed Sequence Tags, Genetic Variation, Molecular Sequence Annotation, Pseudogenes, Transcriptome physiology, Databases, Genetic, Genome, Mammals genetics, Mammals metabolism
- Abstract
Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium.Database URL: http://pangolin-genome.um.edu.my., (© The Author(s) 2016. Published by Oxford University Press.)
- Published
- 2016
- Full Text
- View/download PDF
40. A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts.
- Author
-
Kabir TD, Leigh RJ, Tasena H, Mellone M, Coletta RD, Parkinson EK, Prime SS, Thomas GJ, Paterson IC, Zhou D, McCall J, Speight PM, and Lambert DW
- Subjects
- Cancer-Associated Fibroblasts drug effects, Celecoxib pharmacology, Cell Movement drug effects, Cell Movement physiology, Coculture Techniques, Dinoprostone metabolism, Humans, Phenotype, Signal Transduction drug effects, Up-Regulation, Cancer-Associated Fibroblasts metabolism, Cellular Senescence physiology, Cyclooxygenase 2 metabolism, MicroRNAs metabolism, PTEN Phosphohydrolase metabolism, Signal Transduction physiology
- Abstract
Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
41. Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.
- Author
-
Patmanathan SN, Johnson SP, Lai SL, Panja Bernam S, Lopes V, Wei W, Ibrahim MH, Torta F, Narayanaswamy P, Wenk MR, Herr DR, Murray PG, Yap LF, and Paterson IC
- Subjects
- Aldehyde-Lyases metabolism, Antineoplastic Agents pharmacology, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Line, Cell Line, Tumor, Cell Movement drug effects, Cell Survival drug effects, Cell Survival genetics, Cisplatin pharmacology, Drug Synergism, Female, Fingolimod Hydrochloride pharmacology, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Humans, Immunosuppressive Agents pharmacology, Kaplan-Meier Estimate, Lysophospholipids metabolism, Lysophospholipids pharmacology, Male, Middle Aged, Mouth Neoplasms metabolism, Mouth Neoplasms pathology, Phenotype, Phosphotransferases (Alcohol Group Acceptor) metabolism, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives, Sphingosine metabolism, Sphingosine pharmacology, Sphingosine-1-Phosphate Receptors, Aldehyde-Lyases genetics, Carcinoma, Squamous Cell genetics, Cell Movement genetics, Mouth Neoplasms genetics, Phosphotransferases (Alcohol Group Acceptor) genetics, Receptors, Lysosphingolipid genetics
- Abstract
Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.
- Published
- 2016
- Full Text
- View/download PDF
42. StreptoBase: An Oral Streptococcus mitis Group Genomic Resource and Analysis Platform.
- Author
-
Zheng W, Tan TK, Paterson IC, Mutha NV, Siow CC, Tan SY, Old LA, Jakubovics NS, and Choo SW
- Subjects
- Humans, Genome, Bacterial, Mouth microbiology, Streptococcus mitis genetics
- Abstract
The oral streptococci are spherical Gram-positive bacteria categorized under the phylum Firmicutes which are among the most common causative agents of bacterial infective endocarditis (IE) and are also important agents in septicaemia in neutropenic patients. The Streptococcus mitis group is comprised of 13 species including some of the most common human oral colonizers such as S. mitis, S. oralis, S. sanguinis and S. gordonii as well as species such as S. tigurinus, S. oligofermentans and S. australis that have only recently been classified and are poorly understood at present. We present StreptoBase, which provides a specialized free resource focusing on the genomic analyses of oral species from the mitis group. It currently hosts 104 S. mitis group genomes including 27 novel mitis group strains that we sequenced using the high throughput Illumina HiSeq technology platform, and provides a comprehensive set of genome sequences for analyses, particularly comparative analyses and visualization of both cross-species and cross-strain characteristics of S. mitis group bacteria. StreptoBase incorporates sophisticated in-house designed bioinformatics web tools such as Pairwise Genome Comparison (PGC) tool and Pathogenomic Profiling Tool (PathoProT), which facilitate comparative pathogenomics analysis of Streptococcus strains. Examples are provided to demonstrate how StreptoBase can be employed to compare genome structure of different S. mitis group bacteria and putative virulence genes profile across multiple streptococcal strains. In conclusion, StreptoBase offers access to a range of streptococci genomic resources as well as analysis tools and will be an invaluable platform to accelerate research in streptococci. Database URL: http://streptococcus.um.edu.my.
- Published
- 2016
- Full Text
- View/download PDF
43. Sphingosine 1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death: implications for otoprotective therapy.
- Author
-
Herr DR, Reolo MJ, Peh YX, Wang W, Lee CW, Rivera R, Paterson IC, and Chun J
- Subjects
- Animals, Cell Death genetics, Cell Survival drug effects, Cochlea metabolism, Cochlea pathology, Mice, Mice, Knockout, Receptors, Lysosphingolipid agonists, Receptors, Lysosphingolipid genetics, Signal Transduction drug effects, Reactive Oxygen Species metabolism, Receptors, Lysosphingolipid metabolism
- Abstract
Ototoxic drugs, such as platinum-based chemotherapeutics, often lead to permanent hearing loss through apoptosis of neuroepithelial hair cells and afferent neurons of the cochlea. There is no approved therapy for preventing or reversing this process. Our previous studies identified a G protein-coupled receptor (GPCR), S1P2, as a potential mediator of otoprotection. We therefore sought to identify a pharmacological approach to prevent cochlear degeneration via activation of S1P2. The cochleae of S1pr2(-/-) knockout mice were evaluated for accumulation of reactive oxygen species (ROS) with a nitro blue tetrazolium (NBT) assay. This showed that loss of S1P2 results in accumulation of ROS that precedes progressive cochlear degeneration as previously reported. These findings were supported by in vitro cell-based assays to evaluate cell viability, induction of apoptosis, and accumulation of ROS following activation of S1P2 in the presence of cisplatin. We show for the first time, that activation of S1P2 with a selective receptor agonist increases cell viability and reduces cisplatin-mediated cell death by reducing ROS. Cumulatively, these results suggest that S1P2 may serve as a therapeutic target for attenuating cisplatin-mediated ototoxicity.
- Published
- 2016
- Full Text
- View/download PDF
44. Cell Cycle Arrest and Apoptosis Induction via Modulation of Mitochondrial Integrity by Bcl-2 Family Members and Caspase Dependence in Dracaena cinnabari-Treated H400 Human Oral Squamous Cell Carcinoma.
- Author
-
Alabsi AM, Lim KL, Paterson IC, Ali-Saeed R, and Muharram BA
- Subjects
- Biological Assay, Cell Proliferation drug effects, Cell Shape drug effects, Chemical Fractionation, Cytochromes c metabolism, DNA Fragmentation drug effects, Fibroblasts drug effects, Humans, Inhibitory Concentration 50, Membrane Potential, Mitochondrial drug effects, Mitochondria drug effects, Mouth Neoplasms metabolism, Neoplasms, Squamous Cell metabolism, Nucleosomes drug effects, Nucleosomes metabolism, Phosphatidylserines metabolism, S Phase drug effects, Signal Transduction drug effects, Apoptosis drug effects, Caspases metabolism, Cell Cycle Checkpoints drug effects, Dracaena chemistry, Mitochondria metabolism, Mouth Neoplasms pathology, Neoplasms, Squamous Cell pathology, Plant Extracts pharmacology, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
Dracaena cinnabari Balf.f. is a red resin endemic to Socotra Island, Yemen. Although there have been several reports on its therapeutic properties, information on its cytotoxicity and anticancer effects is very limited. This study utilized a bioassay-guided fractionation approach to determine the cytotoxic and apoptosis-inducing effects of D. cinnabari on human oral squamous cell carcinoma (OSCC). The cytotoxic effects of D. cinnabari crude extract were observed in a panel of OSCC cell lines and were most pronounced in H400. Only fractions DCc and DCd were active on H400 cells; subfractions DCc15 and DCd16 exhibited the greatest cytotoxicity against H400 cells and D. cinnabari inhibited cells proliferation in a time-dependent manner. This was achieved primarily via apoptosis where externalization of phospholipid phosphatidylserine was observed using DAPI/Annexin V fluorescence double staining mechanism studied through mitochondrial membrane potential assay cytochrome c enzyme-linked immunosorbent and caspases activities revealed depolarization of mitochondrial membrane potential (MMP) and significant activation of caspases 9 and 3/7, concomitant with S phase arrest. Apoptotic proteins array suggested that MMP was regulated by Bcl-2 proteins family as results demonstrated an upregulation of Bax, Bad, and Bid as well as downregulation of Bcl-2. Hence, D. cinnabari has the potential to be developed as an anticancer agent.
- Published
- 2016
- Full Text
- View/download PDF
45. The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling.
- Author
-
Hong W, Wang Y, Chang Z, Yang Y, Pu J, Sun T, Kaur S, Sacchettini JC, Jung H, Lin Wong W, Fah Yap L, Fong Ngeow Y, Paterson IC, and Wang H
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Binding Sites, Drug Design, Folic Acid Antagonists metabolism, Folic Acid Antagonists pharmacology, Glycerol chemistry, Glycerol metabolism, Humans, Hydrogen Bonding, Microbial Sensitivity Tests, Molecular Conformation, Mycobacterium tuberculosis drug effects, Protein Structure, Tertiary, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins isolation & purification, Structure-Activity Relationship, Tetrahydrofolate Dehydrogenase genetics, Tetrahydrofolate Dehydrogenase metabolism, Thermodynamics, Folic Acid Antagonists chemistry, Molecular Docking Simulation, Mycobacterium tuberculosis enzymology, Tetrahydrofolate Dehydrogenase chemistry
- Abstract
It is an urgent need to develop new drugs for Mycobacterium tuberculosis (Mtb), and the enzyme, dihydrofolate reductase (DHFR) is a recognised drug target. The crystal structures of methotrexate binding to mt- and h-DHFR separately indicate that the glycerol (GOL) binding site is likely to be critical for the function of mt-DHFR selective inhibitors. We have used in silico methods to screen NCI small molecule database and a group of related compounds were obtained that inhibit mt-DHFR activity and showed bactericidal effects against a test Mtb strain. The binding poses were then analysed and the influence of GOL binding site was studied by using molecular modelling. By comparing the chemical structures, 4 compounds that might be able to occupy the GOL binding site were identified. However, these compounds contain large hydrophobic side chains. As the GOL binding site is more hydrophilic, molecular modelling indicated that these compounds were failed to occupy the GOL site. The most potent inhibitor (compound 6) demonstrated limited selectivity for mt-DHFR, but did contain a novel central core (7H-pyrrolo[3,2-f]quinazoline-1,3-diamine), which may significantly expand the chemical space of novel mt-DHFR inhibitors. Collectively, these observations will inform future medicinal chemistry efforts to improve the selectivity of compounds against mt-DHFR.
- Published
- 2015
- Full Text
- View/download PDF
46. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod.
- Author
-
Patmanathan SN, Yap LF, Murray PG, and Paterson IC
- Subjects
- Drug Delivery Systems, Humans, Phenotype, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Drug Repositioning, Fingolimod Hydrochloride pharmacology
- Abstract
Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Published
- 2015
- Full Text
- View/download PDF
47. (6E,10E) Isopolycerasoidol and (6E,10E) Isopolycerasoidol Methyl Ester, Prenylated Benzopyran Derivatives from Pseuduvaria monticola Induce Mitochondrial-Mediated Apoptosis in Human Breast Adenocarcinoma Cells.
- Author
-
Taha H, Looi CY, Arya A, Wong WF, Yap LF, Hasanpourghadi M, Mohd MA, Paterson IC, and Mohd Ali H
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Apoptosis drug effects, Benzopyrans chemistry, Benzopyrans isolation & purification, Breast Neoplasms metabolism, Breast Neoplasms pathology, Caspases metabolism, Cell Line, Tumor, Cell Membrane Permeability drug effects, Down-Regulation drug effects, Female, Genes, bcl-2 drug effects, Humans, MCF-7 Cells, Magnetic Resonance Spectroscopy, Membrane Potential, Mitochondrial drug effects, Reactive Oxygen Species metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Adenocarcinoma drug therapy, Annonaceae chemistry, Antineoplastic Agents, Phytogenic pharmacology, Benzopyrans pharmacology, Breast Neoplasms drug therapy
- Abstract
Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.
- Published
- 2015
- Full Text
- View/download PDF
48. Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma.
- Author
-
Yap LF, Velapasamy S, Lee HM, Thavaraj S, Rajadurai P, Wei W, Vrzalikova K, Ibrahim MH, Khoo AS, Tsao SW, Paterson IC, Taylor GS, Dawson CW, and Murray PG
- Subjects
- Adenocarcinoma pathology, Adenocarcinoma physiopathology, Carcinoma, Cell Line, Tumor, Cell Movement physiology, Herpesvirus 4, Human physiology, Humans, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms pathology, Phosphoric Diester Hydrolases physiology, Receptors, Lysophosphatidic Acid genetics, T-Lymphocytes, Cytotoxic pathology, Viral Matrix Proteins physiology, Down-Regulation physiology, Epstein-Barr Virus Infections physiopathology, Gene Expression Regulation, Neoplastic physiology, Lysophospholipids physiology, Nasopharyngeal Neoplasms physiopathology, Receptors, Lysophosphatidic Acid physiology, Signal Transduction physiology
- Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.