86 results on '"Ateeq B"'
Search Results
2. Molecular profiling of ETS and non‐ETS aberrations in prostate cancer patients from northern India
- Author
-
Ateeq, B, primary, Kunju, LP, additional, Carskadon, SL, additional, Pandey, SK, additional, Singh, G, additional, Pradeep, I, additional, Tandon, V, additional, Singhai, A, additional, Goel, A, additional, Amit, S, additional, Agarwal, A, additional, Dinda, AK, additional, Seth, A, additional, Tsodikov, A, additional, Chinnaiyan, AM, additional, and Palanisamy, N, additional
- Published
- 2021
- Full Text
- View/download PDF
3. SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression
- Author
-
Tiwari, R, Pandey, S K, Goel, S, Bhatia, V, Shukla, S, Jing, X, Dhanasekaran, S M, and Ateeq, B
- Published
- 2015
- Full Text
- View/download PDF
4. An Integrated Workflow to Close Out the Uncertainties in a Geomechanical Model in a Giant Onshore Carbonate Gas Field in Abu Dhabi, UAE
- Author
-
Masoud, Rashad, additional, Noufal, A.., additional, Ateeq, B.., additional, Al Ammari, K.., additional, El Gohary, M.., additional, Al Hammadi, H.., additional, Kumar, S.., additional, de Joussineau, G.., additional, and Bois, A.., additional
- Published
- 2017
- Full Text
- View/download PDF
5. Innovative Testing for Potential Compaction of Heterogeneous Carbonate Reservoir in A Giant Field, Abu Dhabi, UAE
- Author
-
Noufal, A.., additional, Ateeq, B.., additional, Al Amari, K.., additional, Masoud, R.., additional, Al Gohary, M.., additional, Sirat, M.., additional, Bois, A.-P.. -P., additional, Dadouche, H.., additional, Kpatta, D.., additional, and Mohajerani, M.., additional
- Published
- 2017
- Full Text
- View/download PDF
6. The Soldier and the Animal: metaphor in maintenance of antiretroviral adherence in Ghana’s Eastern Region
- Author
-
Akiyama, Matthew J., Napier, David, Bourque, S., Goldberg, A., Boukh-Viner, T., Gregg, C., Kyryakov, P., Chowdhury, S., Titorenko, V.I., Andrews, S.D., Ateeq, B., Torrisani, J., D’Allesio, A.C., Unterberger, A., OU, J-N, McKinney, A., Rabbani, S., Szyf, M., Berger, Robert G., Hancock, Trina, Decatanzaro, Denys, Antonova, Lilia, Mueller, Christopher R., Fong, Jenna, Bañski, Piotr, Kodiha, Mohamed, Stochaj, Ursula, Moheshwarnath, Issur, Bisaillon, Martin, Brisbin, Sarah E., Chin-Sang, Ian D., Ste-Marie, A., Simard, C., Côté, S., Fucile, S, Gisel, E, Erg, Otr, Lau, C, Bourdeau, Annie, Heinonen, Krista M., Doody, Karen M., Higgins, Emily K., Lee-Loy, Ailsa, Tremblay, Michel L., Banski, Piotr, Leduc, F., Maquennehan, V., Nkoma, G. Bikond, Boissonneault, G., Lim, Letitia Z., Hacking, S. A., Li, A., Wang, H., Harvey, E. J., Henderson, J. E., Prefontaine, D., Lajoie-Kadoch, S., Mogas, A.K., Foley, S., Olivenstein, R., Halayko, A.J., Ernst, P., Lemière, C., Martin, J.G., Hamid, Q., McKillop, W. M., Dekaban, G. A., Nguyen, Alana, Beland, Melanie, Gaitan, Yaned, Bouchard, Maxime, Behrmann, Jason, Williams-Jones, Bryn, Hakonarson, Hakon, Grant, Struan F.A., Bradfield, Jonathan P., Marchand, Luc, Kim, Cecilia E., Glessner, Joseph T., Grabs, Rosemarie, Casalunovo, Tracy, Taback, Shayne P., Frackelton, Edward C., Lawson, Margaret L., Robinson, Luke J., Capasso, Mario, Skraban, Robert, Lu, Yang, Chiavacci, Rosetta M., Stanley, Charles A., Kirsch, Susan E., Monos, Dimitri S., Devoto, Marcella, Qu, Hui-Qi, Polychronakos, Constantin, Proulx, Dominic Paquin, Lemieux, Réal, Bazin, Renée, Richard, Nathalie, Tseu, Irene, Post, Martin, Radina, M, Penner, MJ, Smith, RG, Samdup, D, Sebak, Safaa, Mirzaei, Maryam, Malhotra, Meenakshi, Kulamarva, Arun, Prakash, Satya, Tzankov, S., Bhangoo, M. K., Fan, A.C.Y., Young, J.C., Arulanandam, Rozanne, Cao, Jun, Vultur, Adina, Degeer, Jonathan, Larue, Lionel, Feracci, Hélène, Raptis, Leda, Vi, Linda, Gan, Bing Siang, O’gorman, David, Shao, W., and Saleh, M.
- Subjects
cell division ,implant osseo-integration ,caspase-3 ,Bisphenol-A ,heterokaryons ,Ghana ,Hsp70 ,stress ,VAB-1 Eph Receptor ,bone regeneration ,protein folding ,Rho GTPases ,antibodies ,implantation ,adherence ,oncogenic signaling ,Hsc70s ,polyploidy ,genomic integrity ,topoisomerase ,fertility ,shuttling ,airway smooth muscle cells ,Calcineurin ,ADAM12 ,apoptosis ,tyrosine kinase ,cell signalling ,CnABP ,single-nucleotide polymorphism ,developmental delay ,Type 1 diabetes ,cell-cell adhesion ,tissue engineering ,protein tyrosine phosphatase-1B ,confluence ,C. elegans ,CSLSR Abstracts ,pregnancy ,interleukin 33 ,stretch ,estrogens ,RAS activation ,tumour suppressor ,antiretroviral therapy ,DNA repair ,autism ,Hsp90 ,Dupuytren’s Disease ,DAF-18/PTEN ,Wilms’ tumor ,intersferon-gamma ,idiopathic toe walking ,Hsc70 ,cytochrome C ,megakaryocytes ,metastasis ,ADHD ,chaperones ,IGF ,nucleoli ,nucleolar targeting ,epigenetics ,uterus ,Pax2 ,Stat3 ,nucleus ,HIV ,Krobo ,illness narrative ,demethylation ,asthma ,osteoporosis ,bronchial biopsies ,hematopoiesis ,spermiogenesis ,T cell protein tyrosine phosphatase ,cadherin ,blood platelet production ,inflammation ,genome-wide association ,Abstracts from CSLSR ,chromatin ,accumulation ,mitochondrial import - Published
- 2007
7. Targeted Radiosensitization of ETS Gene Fusion-Positive Prostate Cancer
- Author
-
Sabolch, A., primary, Brenner, J.C., additional, Ateeq, B., additional, Li, Y., additional, Yocum, A., additional, Davis, M., additional, Hamstra, D.A., additional, Chinnaiyan, A.M., additional, Lawrence, T.S., additional, and Feng, F.Y., additional
- Published
- 2010
- Full Text
- View/download PDF
8. An Integrated Approach for Assessment of Water Holdup in a Multilayer Carbonate Reservoir
- Author
-
Abdelmawla, A., additional, Dabbouk, C., additional, Urasaki, D., additional, Ateeq, B., additional, and Kutty, A. R., additional
- Published
- 2005
- Full Text
- View/download PDF
9. Differential gene expression in human Lung Squamous Cell Carcinoma in Asian Indians may help to identify genetic predisposition
- Author
-
Sen, S., Ateeq, B., Sharma, H., Datta, P., Bal, S., Kumar, A., and Singh, N.
- Published
- 2006
- Full Text
- View/download PDF
10. The Role of Sarcosine Metabolism in Prostate Cancer Progression
- Author
-
Amjad P Khan, Thekkelnaycke M Rajendiran, Ateeq Bushra, Irfan A Asangani, Jyoti N Athanikar, Anastasia K Yocum, Rohit Mehra, Javed Siddiqui, Ganesh Palapattu, John T Wei, George Michailidis, Arun Sreekumar, and Arul M Chinnaiyan
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Metabolomic profiling of prostate cancer (PCa) progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic PCa and modest but significant elevation of the metabolite in PCa urine. Here, we examine the role of key enzymes associated with sarcosine metabolism in PCa progression. Consistent with our earlier report, sarcosine levels were significantly elevated in PCa urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71. In addition, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in PCa tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Accordingly, addition of sarcosine, but not glycine or alanine, induced invasion and intravasation in an in vivo PCa model. In contrast, GNMT knockdown or SARDH overexpression in PCa xenografts inhibited tumor growth. Taken together, these studies substantiate the role of sarcosine in PCa progression.
- Published
- 2013
- Full Text
- View/download PDF
11. Induction of micronuclei and erythrocyte alterations in the catfish Clarias batrachus by 2,4-dichlorophenoxyacetic acid and butachlor
- Author
-
Ateeq, B
- Published
- 2002
- Full Text
- View/download PDF
12. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer.
- Author
-
Wang X, Qiao Y, Asangani IA, Ateeq B, Poliakov A, Cieślik M, Pitchiaya S, Chakravarthi BVSK, Cao X, Jing X, Wang CX, Apel IJ, Wang R, Ching-Yi Tien J, Juckette KM, Yan W, Jiang H, Wang S, Varambally S, and Chinnaiyan AM
- Published
- 2024
- Full Text
- View/download PDF
13. An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.
- Author
-
Manzar N, Khan UK, Goel A, Carskadon S, Gupta N, Palanisamy N, and Ateeq B
- Abstract
Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderate levels of KIT expression were detected in ∼85% of SPINK1-positive PCa specimens. We show KIT signaling orchestrates SPINK1-mediated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/β-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling led to restoration of AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide distinct treatment modalities for advanced-stage SPINK1-positive patients., Competing Interests: N.P. is a consultant to Astrazeneca., (© 2024 The Authors.)
- Published
- 2024
- Full Text
- View/download PDF
14. Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.
- Author
-
Yadav A, Biswas T, Praveen A, Ganguly P, Bhattacharyya A, Verma A, Datta D, and Ateeq B
- Subjects
- Male, Humans, Animals, Mice, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Homologous Recombination genetics, RNA, Long Noncoding genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, MicroRNAs
- Abstract
PARP inhibitors (PARPi) have emerged as a promising targeted therapeutic intervention for metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi is limited to a subset of patients who harbor aberrations in the genes associated with the homologous recombination (HR) pathway. Here, we report that targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an oncogenic long noncoding RNA (lncRNA), contrives a BRCAness-like phenotype, and augments sensitivity to PARPi. Mechanistically, we show that MALAT1 silencing reprograms the homologous recombination (HR) transcriptome and makes prostate cancer cells more vulnerable to PARPi. Particularly, coinhibition of MALAT1 and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci, and reduces tumor burden in mice xenograft model. Moreover, we show that miR-421, a tumor suppressor miRNA, negatively regulates the expression of HR genes, while in aggressive prostate cancer cases, miR-421 is sequestered by MALAT1, leading to increased expression of HR genes. Conclusively, our findings suggest that MALAT1 ablation confers sensitivity to PARPi, thus highlighting an alternative therapeutic strategy for patients with castration-resistant prostate cancer (CRPC), irrespective of the alterations in HR genes., Significance: PARPi are clinically approved for patients with metastatic CRPC carrying mutations in HR genes, but are ineffective for HR-proficient prostate cancer. Herein, we show that oncogenic lncRNA, MALAT1 is frequently overexpressed in advanced stage prostate cancer and plays a crucial role in maintaining genomic integrity. Importantly, we propose a novel therapeutic strategy that emphasizes MALAT1 inhibition, leading to HR dysfunction in both HR-deficient and -proficient prostate cancer, consequently augmenting their susceptibility to PARPi., (© 2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
15. Transcription networks rewire gene repertoire to coordinate cellular reprograming in prostate cancer.
- Author
-
Manzar N, Ganguly P, Khan UK, and Ateeq B
- Subjects
- Male, Humans, Chromatin, Gene Regulatory Networks, Disease Progression, Transcription Factors genetics, Transcription Factors metabolism, Prostatic Neoplasms genetics
- Abstract
Transcription factors (TFs) represent the most commonly deregulated DNA-binding class of proteins associated with multiple human cancers. They can act as transcriptional activators or repressors that rewire the cistrome, resulting in cellular reprogramming during cancer progression. Deregulation of TFs is associated with the onset and maintenance of various cancer types including prostate cancer. An emerging subset of TFs has been implicated in the regulation of multiple cancer hallmarks during tumorigenesis. Here, we discuss the role of key TFs which modulate transcriptional cicuitries involved in the development and progression of prostate cancer. We further highlight the role of TFs associated with key cancer hallmarks, including, chromatin remodeling, genome instability, DNA repair, invasion, and metastasis. We also discuss the pluripotent function of TFs in conferring lineage plasticity, that aids in disease progression to neuroendocrine prostate cancer. At the end, we summarize the current understanding and approaches employed for the therapeutic targeting of TFs and their cofactors in the clinical setups to prevent disease progression., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
16. Human ERG oncoprotein represses a Drosophila LIM domain binding protein-coding gene Chip .
- Author
-
Bharti M, Bajpai A, Rautela U, Manzar N, Ateeq B, and Sinha P
- Subjects
- Male, Animals, Humans, Oligonucleotide Array Sequence Analysis, Transcription Factors metabolism, Oncogene Proteins metabolism, Transcriptional Regulator ERG genetics, Transcriptional Regulator ERG metabolism, Drosophila genetics, Drosophila Proteins genetics, Drosophila Proteins metabolism
- Abstract
Human E TS R elated G ene, ERG, a master transcription factor, turns oncogenic upon its out-of-context activation in diverse developmental lineages. However, the mechanism underlying its lineage-specific activation of Notch (N), Wnt, or EZH2-three well-characterized oncogenic targets of ERG-remains elusive. We reasoned that deep homology in genetic tool kits might help uncover such elusive cancer mechanisms in Drosophila . By heterologous gain of human ERG in Drosophila , here we reveal Chip, which codes for a transcriptional coactivator, LIM-domain-binding (LDB) protein, as its novel target. ERG represses Drosophila Chip via its direct binding and, indirectly, via E(z)-mediated silencing of its promoter. Downregulation of Chip disrupts LIM-HD complex formed between Chip and Tailup (Tup)-a LIM-HD transcription factor-in the developing notum. A consequent activation of N-driven Wg signaling leads to notum-to-wing transdetermination. These fallouts of ERG gain are arrested upon a simultaneous gain of Chip, sequestration of Wg ligand, and, alternatively, loss of N signaling or E(z) activity. Finally, we show that the human LDB1 , a homolog of Drosophila Chip , is repressed in ERG-positive prostate cancer cells. Besides identifying an elusive target of human ERG, our study unravels an underpinning of its lineage-specific carcinogenesis.
- Published
- 2023
- Full Text
- View/download PDF
17. Red-emitting polyaniline-based nanoparticle probe for pH-sensitive fluorescence imaging.
- Author
-
Yadav L, Yadav A, Chatterjee S, Tyeb S, Gupta RK, Sen P, Ateeq B, Verma V, and Nalwa KS
- Subjects
- Aniline Compounds, Fluorescent Dyes, Humans, Hydrogen-Ion Concentration, Male, Optical Imaging, Nanoparticles, Prostatic Neoplasms
- Abstract
Fluorescent probes based on semiconducting polymer nanoparticles (NPs) such as polyaniline (PANI) usually require external fluorophore doping to provide fluorescence function. Direct use of PANI-based NPs for bioimaging applications has been limited by PANI's weak blue fluorescence and aggregation-induced quenching in physiological medium. In this report, we developed a facile solid-state synthesis method to produce fluorescent polyaniline nanoparticles (FPNs) that are not only water-soluble but also exhibit high intensity and pH-sensitive red fluorescence. The FPNs showed high photoluminescence quantum yield (PLQY) of 19.3 % at physiological pH, which makes FPNs ideal for application as fluorescent nanoprobes in bioimaging. Moreover, we performed an in-depth study of photoluminescence dependence on pH and the phenomena of exciton-polaron quenching at low pH was highlighted. We also found that the ratio of emission intensity at 600 nm and 650 nm increased from 0.04 to 1.65 as pH was raised from 2.6 to 11.8, which could find its application in ratiometric pH sensing. FPNs exhibited excellent biocompatibility with >85 % cell viability for fibroblasts NIH/3 T3 and prostate cancer 22RV1 cells even at concentrations as high as 1000 μg/mL. In addition, fluorescence microscopy demonstrated concentration-dependent red fluorescence in the cytoplasm owing to the cellular uptake of FPNs in prostate cancer cells., 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 © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
18. Epigenetic reprogramming during prostate cancer progression: A perspective from development.
- Author
-
Goel S, Bhatia V, Biswas T, and Ateeq B
- Subjects
- Cell Differentiation genetics, Cellular Reprogramming genetics, Epigenesis, Genetic, Epigenomics, Humans, Male, Prostate, Prostatic Neoplasms genetics
- Abstract
Conrad Waddington's theory of epigenetic landscape epitomize the process of cell fate and cellular decision-making during development. Wherein the epigenetic code maintains patterns of gene expression in pluripotent and differentiated cellular states during embryonic development and differentiation. Over the years disruption or reprogramming of the epigenetic landscape has been extensively studied in the course of cancer progression. Cellular dedifferentiation being a key hallmark of cancer allow us to take cues from the biological processes involving epigenetic reprogramming in development such as the cellular differentiation and morphogenesis. Here, we discuss the role of epigenetic landscape and its modifiers in cell-fate determination, differentiation and prostate cancer progression. Lately, the emergence of RNA-modifications has also furthered our understanding of epigenetics in cancer. The overview of the epigenetic code regulating androgen signalling, and progression to aggressive neuroendocrine stage of PCa reinforces its gene regulatory functions during the development of prostate gland as well as cancer progression. Additionally, we also highlight the clinical implications of cancer cell epigenome, and discuss the recent advancements in the therapeutic strategies targeting the advanced stage disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
19. Nuclear magnetic resonance spectroscopy reveals dysregulation of monounsaturated fatty acid metabolism upon SPINK1 attenuation in colorectal cancer.
- Author
-
Nigam S, Ranjan R, Sinha N, and Ateeq B
- Subjects
- Fatty Acids, Monounsaturated metabolism, Humans, Magnetic Resonance Spectroscopy, Colorectal Neoplasms pathology, Lipid Metabolism, Trypsin Inhibitor, Kazal Pancreatic metabolism
- Abstract
Metabolic reprogramming, a key hallmark of cancer, plays a pivotal role in fulfilling the accelerated biological demands of tumor cells. Such metabolic changes trigger the production of several proinflammatory factors, thereby inciting cancer development and its progression. Serine protease inhibitor Kazal Type 1 (SPINK1), well known for its oncogenic role and its upregulation via acute-phase reactions, is highly expressed in multiple cancers including colorectal cancer (CRC). Here, we show accumulation of lipid droplets in CRC cells stained with Oil Red O upon SPINK1 silencing. Furthermore, NMR spectroscopy analysis revealed an accretion of monounsaturated fatty acids (MUFAs) and phosphatidylcholine in these CRC cells, while the levels of polyunsaturated fatty acids remained unaltered. This alteration indicates the presence of MUFAs with the triglycerides in the lipid droplets as observed in SPINK1-silenced CRC cells. Considering the role of MUFAs in the anti-inflammatory response, our data hint that suppression of SPINK1 in CRC leads to activation of an anti-inflammatory signaling milieu. Conclusively, our study uncovers a connection between lipid metabolism and SPINK1-mediated CRC progression, hence paving the way for further exploration and better prognosis of SPINK1-positive CRC patients., (© 2022 John Wiley & Sons, Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
20. Corrigendum to "Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo" [Neoplasia 10/3 (2008) 266-278].
- Author
-
Ateeq B, Unterberger A, Szyf M, and ARabbani S
- Published
- 2022
- Full Text
- View/download PDF
21. Untargeted Metabolomics Showed Accumulation of One-Carbon Metabolites to Facilitate DNA Methylation during Extracellular Matrix Detachment of Cancer Cells.
- Author
-
Nur SM, Shait Mohammed MR, Zamzami MA, Choudhry H, Ahmad A, Ateeq B, Rather IA, and Khan MI
- Abstract
Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, a global substrate for methylation reactions, especially DNA methylation. DNA methylation-mediated repression of NK cell ligands MICA and MICB during ECM detachment has been overlooked. In the current work, we quantitated the impact of ECM detachment on one-carbon metabolites, expression of 1C regulatory pathway genes, and total methylation levels. Our results showed that ECM detachment promotes the accumulation of one-carbon metabolites and induces regulatory pathway genes and total DNA methylation. Furthermore, we measured the expression of well-known targets of DNA methylation in NK cell ligands in cancer cells, namely, MICA/B, during ECM detachment and observed low expression compared to ECM-attached cancer cells. Finally, we treated the ECM-detached cancer cells with vitamin C (a global methylation inhibitor) and observed a reduction in the promoter methylation of NK cell ligands, resulting in MICA/B re-expression. Treatment with vitamin C was also found to reduce global DNA methylation levels in ECM-detached cancer cells.
- Published
- 2022
- Full Text
- View/download PDF
22. The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes.
- Author
-
Shait Mohammed MR, Zamzami M, Choudhry H, Ahmed F, Ateeq B, and Khan MI
- Abstract
Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis's specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone demethylases are involved in promoting or resisting anoikis remains elusive. We screened the major histone demethylases and found that both H3K27 histone demethylases, namely, KDM6A/B were highly expressed during ECM detachment. Inhibition of the KDM6A/B activity by using a specific inhibitor results in reduced sphere formation capacity and increased apoptosis. Knockout of KDM6B leads to the loss of stem cell properties in solitary cells. Furthermore, we found that KDM6B maintains stemness by transcriptionally regulating the expression of stemness genes SOX2 , SOX9 , and CD44 in detached cells. KDM6B occupies the promoter region of both SOX2 and CD44 to regulate their expression epigenetically. We also noticed an increased occupancy of the HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in detached cancer cells. This observation was further strengthened as we found a significant positive association in the expression of both KDM6B and HIF1α in various cancer types. Overall, our results reveal a novel transcriptional program that regulates resistance against anoikis and maintains stemness-like properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shait Mohammed, Zamzami, Choudhry, Ahmed, Ateeq and Khan.)
- Published
- 2022
- Full Text
- View/download PDF
23. Transcriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression.
- Author
-
Goel S, Bhatia V, Kundu S, Biswas T, Carskadon S, Gupta N, Asim M, Morrissey C, Palanisamy N, and Ateeq B
- Subjects
- Androgen Antagonists pharmacology, Animals, Azepines pharmacology, Cell Line, Tumor, Disease Progression, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Homeodomain Proteins metabolism, Humans, Male, Mice, Mice, Knockout, Mice, SCID, Neoplasm Metastasis, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Promoter Regions, Genetic, Prostate drug effects, Prostate metabolism, Prostate pathology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, Protein Binding, Receptors, Androgen metabolism, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Signal Transduction, Survival Analysis, Transcription Factors metabolism, Transcriptional Regulator ERG genetics, Transcriptional Regulator ERG metabolism, Triazoles pharmacology, Xenograft Model Antitumor Assays, Homeodomain Proteins genetics, Prostatic Neoplasms genetics, Receptors, Androgen genetics, Transcription Factors genetics, Transcription, Genetic
- Abstract
Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulate DLX1. Notably, inhibiting ERG/AR-mediated DLX1 transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishes DLX1 as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
24. Nutritive vitamins as epidrugs.
- Author
-
Nur SM, Rath S, Ahmad V, Ahmad A, Ateeq B, and Khan MI
- Subjects
- DNA Methylation, Epigenesis, Genetic, Histones metabolism, Vitamin A, Vitamins pharmacology
- Abstract
Epigenetic modifications play an important role in disease pathogenesis and therefore are a focus of intense investigation. Epigenetic changes include DNA, RNA, and histone modifications along with expression of non-coding RNAs. Various factors such as environment, diet, and lifestyle can influence the epigenome. Dietary nutrients like vitamins can regulate both physiological and pathological processes through their direct impact on epigenome. Vitamin A acts as a major regulator of above-mentioned epigenetic mechanisms. B group vitamins including biotin, niacin, and pantothenic acid also participate in modulation of various epigenome. Further, vitamin C has shown to modulate both DNA methylation and histone modifications while few reports have also supported its role in miRNA-mediated pathways. Similarly, vitamin D also influences various epigenetic modifications of both DNA and histone by controlling the regulatory mechanisms. Despite the information that vitamins can modulate the epigenome, the detailed mechanisms of vitamin-mediated epigenetic regulations have not been explored fully and hence further detailed studies are required to decipher their role at epigenome level in both normal and disease pathogenesis. The current review summarizes the available literature on the role of vitamins as epigenetic modifier and highlights the key evidences for developing vitamins as potential epidrugs.
- Published
- 2021
- Full Text
- View/download PDF
25. Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X L : Role of Non-Hot Spot Residues.
- Author
-
Reddy CN, Manzar N, Ateeq B, and Sankararamakrishnan R
- Subjects
- Amino Acid Sequence, Humans, MCF-7 Cells, Models, Molecular, Myeloid Cell Leukemia Sequence 1 Protein chemistry, Protein Binding, Protein Domains, Substrate Specificity, bcl-X Protein chemistry, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Peptidomimetics chemistry, Peptidomimetics pharmacology, bcl-X Protein antagonists & inhibitors, bcl-X Protein metabolism
- Abstract
Interactions between pro- and anti-apoptotic Bcl-2 proteins decide the fate of the cell. The BH3 domain of pro-apoptotic Bcl-2 proteins interacts with the exposed hydrophobic groove of their anti-apoptotic counterparts. Through their design and development, BH3 mimetics that target the hydrophobic groove of specific anti-apoptotic Bcl-2 proteins have the potential to become anticancer drugs. We have developed a novel computational method for designing sequences with BH3 domain features that can bind specifically to anti-apoptotic Mcl-1 or Bcl-X
L . In this method, we retained the four highly conserved hydrophobic and aspartic residues of wild-type BH3 sequences and randomly substituted all other positions to generate a large number of BH3-like sequences. We modeled 20000 complex structures with Mcl-1 or Bcl-XL using the BH3-like sequences derived from five wild-type pro-apoptotic BH3 peptides. Peptide-protein interaction energies calculated from these models for each set of BH3-like sequences resulted in negatively skewed extreme value distributions. The selected BH3-like sequences from the extreme negative tail regions have highly favorable interaction energies with Mcl-1 or Bcl-XL . They are enriched in acidic and basic residues when they bind to Mcl-1 and Bcl-XL , respectively. With the charged residues often away from the binding interface, the overall electric field generated by the charged residues results in strong long-range electrostatic interaction energies between the peptide and the protein giving rise to high specificity. Cell viability studies of representative BH3-like peptides further validated the predicted specificity. This study has revealed the importance of non-hot spot residues in BH3-mimetic peptides in providing specificity to a particular anti-apoptotic protein.- Published
- 2020
- Full Text
- View/download PDF
26. Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma.
- Author
-
Singh A, Srivastava N, Yadav A, and Ateeq B
- Subjects
- Animals, Apoptosis, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Movement, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma metabolism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, NF-kappa B genetics, Receptor, Angiotensin, Type 1 genetics, Receptors, CXCR4 genetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms pathology, Glioblastoma pathology, MicroRNAs genetics, NF-kappa B metabolism, Receptor, Angiotensin, Type 1 metabolism, Receptors, CXCR4 metabolism
- Abstract
Glioblastoma (GBM) represents the most aggressive malignancy of the central nervous system. Increased expression of Angiotensin II Receptor Type 1 (AGTR1) has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3'untranslated region (3'UTR) of AGTR1 for putative miRNA binding by using prediction algorithms. Interestingly, miR-155 showed conserved binding on the 3'UTR of AGTR1, subsequently confirmed by luciferase reporter assay. Furthermore, miR-155 overexpressing GBM cells show decrease in AGTR1 expression accompanied with reduced cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show negligible tumor growth. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 as well as AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated angiogenesis, epithelial-to-mesenchymal transition, stemness, and MAPK signaling. Similar effects were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex in multiple cell-based assays. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects in GBM. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies., 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 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
27. A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors.
- Author
-
Bajpai A, Quazi TA, Tang HW, Manzar N, Singh V, Thakur A, Ateeq B, Perrimon N, and Sinha P
- Subjects
- Administration, Oral, Animals, Animals, Genetically Modified, Antineoplastic Agents metabolism, Cell Proliferation drug effects, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Drug Screening Assays, Antitumor, Female, Gene Expression Regulation, Neoplastic, Humans, Intestinal Neoplasms genetics, Intestinal Neoplasms metabolism, Intestinal Neoplasms pathology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Nuclear Proteins genetics, Nuclear Proteins metabolism, PC-3 Cells, Peptide Fragments genetics, Peptide Fragments metabolism, Signal Transduction, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors genetics, Transcription Factors metabolism, YAP-Signaling Proteins, Antineoplastic Agents administration & dosage, DNA-Binding Proteins administration & dosage, Drosophila melanogaster drug effects, Drug Development, Intestinal Neoplasms drug therapy, Neoplastic Stem Cells drug effects, Peptide Fragments administration & dosage, Transcription Factors administration & dosage
- Abstract
Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
28. Toxicity of exhaust particulates and gaseous emissions from gasohol (ethanol blended gasoline)-fuelled spark ignition engines.
- Author
-
Agarwal AK, Singh AP, Gupta T, Agarwal RA, Sharma N, Pandey SK, and Ateeq B
- Subjects
- Ethanol, Gases, Particulate Matter, Air Pollutants, Gasoline, Vehicle Emissions
- Abstract
In the last couple of decades, blending of oxygenated additives with gasoline has been advocated to reduce dependence on fossil fuels and to reduce hazardous health effects of gaseous emissions and particulate matter (PM) emitted by internal combustion (IC) engines in the transport sector worldwide. The primary objective of this research was to carry out a comparative analysis of exhaust PM emitted by gasohol (gasoline blended with 10% ethanol, v/v)-fulled spark ignition (SI) engine with that of baseline gasoline-fuelled SI engine. To assess the PM toxicity, physical, chemical and biological characterizations of PM were carried out using the state-of-the-art instruments and techniques. Measurements of regulated and unregulated gaseous species were also carried out at part/full loads. The results showed that the gasohol-fuelled engine emitted relatively lower concentrations of unregulated gaseous species such as sulfur dioxide (SO2), isocyanic acid (HNCO), etc. Physical characterization of exhaust particles revealed that the gasohol-fuelled engine emitted a significantly lower number of particles compared to the gasoline-fuelled engine. The presence of harmful polycyclic aromatic hydrocarbons (PAHs) and higher trace metal concentrations in PM emitted from the gasoline-fuelled engine was another important finding of this study. Biological characterizations showed that PM emitted from the gasohol-fuelled engine were less cytotoxic and had lower reactive oxygen species (ROS) generation potential. Mutagenicity of PM emitted from the gasohol-fuelled engine was also lower compared to that from the gasoline-fuelled engine. Overall, this study demonstrated that utilization of gasohol in SI engines led to the reduction in emissions, and lowering of PM toxicity, in addition to partial replacement of fossil fuels with renewable fuels.
- Published
- 2020
- Full Text
- View/download PDF
29. Dynamics of Cellular Plasticity in Prostate Cancer Progression.
- Author
-
Tiwari R, Manzar N, and Ateeq B
- Abstract
Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic regulators, while cell-extrinsic factors include microenvironmental cues and drug-induced selective pressure. Epithelial-mesenchymal transition (EMT) and stemness are two important hallmarks that dictate cellular plasticity in multiple cancer types including prostate. Emerging evidence has also pinpointed the role of tumor cell plasticity in driving anti-androgen induced neuroendocrine prostate cancer (NEPC), a lethal and therapy-resistant subtype. In this review, we discuss the role of cellular plasticity manifested due to genetic, epigenetic alterations and cues from the tumor microenvironment, and their role in driving therapy resistant prostate cancer., (Copyright © 2020 Tiwari, Manzar and Ateeq.)
- Published
- 2020
- Full Text
- View/download PDF
30. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer.
- Author
-
Tiwari R, Manzar N, Bhatia V, Yadav A, Nengroo MA, Datta D, Carskadon S, Gupta N, Sigouros M, Khani F, Poutanen M, Zoubeidi A, Beltran H, Palanisamy N, and Ateeq B
- Subjects
- Androgen Receptor Antagonists therapeutic use, Animals, Casein Kinase I antagonists & inhibitors, Casein Kinase I metabolism, Cell Line, Tumor, Co-Repressor Proteins metabolism, HEK293 Cells, Humans, Male, Mice, Nerve Tissue Proteins metabolism, Neuroendocrine Tumors drug therapy, Neuroendocrine Tumors pathology, Prostate drug effects, Prostate pathology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Receptors, Androgen metabolism, SOXB1 Transcription Factors metabolism, Transcription, Genetic drug effects, Up-Regulation drug effects, Xenograft Model Antitumor Assays, Androgen Receptor Antagonists pharmacology, Gene Expression Regulation, Neoplastic drug effects, Neuroendocrine Tumors genetics, Prostatic Neoplasms genetics, Trypsin Inhibitor, Kazal Pancreatic metabolism
- Abstract
Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.
- Published
- 2020
- Full Text
- View/download PDF
31. Molecular Underpinnings Governing Genetic Complexity of ETS-Fusion-Negative Prostate Cancer.
- Author
-
Bhatia V and Ateeq B
- Subjects
- Cyclin-Dependent Kinases genetics, DNA Repair, ETS Motif genetics, Epigenetic Repression, Gene Expression Regulation, Neoplastic, Genomics, Humans, Loss of Heterozygosity, Male, Nuclear Proteins metabolism, Phosphatidylethanolamine Binding Protein pharmacology, Piperazines therapeutic use, Poly (ADP-Ribose) Polymerase-1 drug effects, Precision Medicine trends, Proteomics, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-raf genetics, Proto-Oncogene Proteins c-raf metabolism, Pyrimidines therapeutic use, Repressor Proteins metabolism, Signal Transduction, Trypsin Inhibitor, Kazal Pancreatic metabolism, Molecular Targeted Therapy trends, Nuclear Proteins genetics, Poly (ADP-Ribose) Polymerase-1 metabolism, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms therapy, Repressor Proteins genetics, Trypsin Inhibitor, Kazal Pancreatic genetics
- Abstract
Inter- and intra-patient molecular heterogeneity of primary and metastatic prostate cancer (PCa) confers variable clinical outcome and poses a formidable challenge in disease management. High-throughput integrative genomics and functional approaches have untangled the complexity involved in this disease and revealed a spectrum of diverse aberrations prevalent in various molecular subtypes, including ETS fusion negative. Emerging evidence indicates that SPINK1 upregulation, mutations in epigenetic regulators or chromatin modifiers, and SPOP are associated with the ETS-fusion negative subtype. Additionally, patients with defects in a DNA-repair pathway respond to poly-(ADP-ribose)-polymerase (PARP) inhibition therapies. Furthermore, a new class of immunogenic subtype defined by CDK12 biallelic loss has also been identified in ETS-fusion-negative cases. This review focuses on the emerging molecular underpinnings driving key oncogenic aberrations and advancements in therapeutic strategies of this disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
32. Caspase-3 mediated programmed cell death by a gold-stabilised peptide carbene.
- Author
-
Gupta A, Nigam S, Avasthi I, Sharma B, Ateeq B, and Verma S
- Subjects
- A549 Cells, Amino Acids chemistry, Caspase 3 metabolism, Coordination Complexes metabolism, Density Functional Theory, Fluorescent Dyes chemistry, Humans, Ligands, MCF-7 Cells, Methane chemistry, Methane metabolism, Models, Molecular, Molecular Structure, Optical Imaging, Peptides metabolism, Apoptosis drug effects, Caspase 3 chemistry, Coordination Complexes chemical synthesis, Gold chemistry, Methane analogs & derivatives, Peptides chemistry
- Abstract
The synthesis of novel N-heterocyclic carbene complexes derived from a tripeptide ligand (L), containing non-natural amino acid, thiazolylalanine is described here. The peptide ligand was reacted with suitable precursors to generate gold and mercury carbene complexes. The plausible structures of both complexes were predicted by spectroscopic data and DFT calculations. The binding energy data was also analyzed to predict their stability. The gold carbene complex (1A), showed activity against MCF7 breast cancer cell line due to mitochondrial triggered caspase-3 mediated programmed cell death. Its internalization inside cells could be observed due to autofluorescence. This study affords a methodology for successful generation of peptide carbene complexes for their therapeutic potential., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
33. Correction to "Direct Intranuclear Anticancer Drug Delivery via Polydimethylsiloxane Nanoparticles: In Vitro and In Vivo Xenograft Studies".
- Author
-
Mishra G, Bhattacharyya S, Bhatia V, Ateeq B, Sharma A, and Sivakumar S
- Published
- 2019
- Full Text
- View/download PDF
34. Implications of the circular RNAs in localized prostate cancer.
- Author
-
Nigam S, Manzar N, and Ateeq B
- Abstract
Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
- Published
- 2019
- Full Text
- View/download PDF
35. Epigenetic Silencing of miRNA-338-5p and miRNA-421 Drives SPINK1-Positive Prostate Cancer.
- Author
-
Bhatia V, Yadav A, Tiwari R, Nigam S, Goel S, Carskadon S, Gupta N, Goel A, Palanisamy N, and Ateeq B
- Subjects
- Animals, Cell Line, Tumor, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Trypsin Inhibitor, Kazal Pancreatic genetics, MicroRNAs, Prostatic Neoplasms genetics
- Abstract
Purpose: Serine peptidase inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in prostate cancer remains largely unknown., Experimental Design: miRNA prediction tools were employed to examine the SPINK1- 3'UTR for miRNA binding. Luciferase reporter assays were performed to confirm the SPINK1- 3'UTR binding of shortlisted miR-338-5p/miR-421. Furthermore, miR-338-5p/-421-overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and a mouse xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. IHC and RNA in situ hybridization were carried out on prostate cancer patients' tissue microarray for SPINK1 and EZH2 expression, respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421-regulatory regions. Bisulfite sequencing and methylated DNA immunoprecipitation were performed on prostate cancer cell lines and patients' specimens., Results: We established a critical role of miRNA-338-5p/-421 in posttranscriptional regulation of SPINK1 . Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive cells abrogates oncogenic properties including cell-cycle progression, stemness, and drug resistance, and shows reduced tumor burden and distant metastases in a mouse model. Importantly, we show that patients with SPINK1-positive prostate cancer exhibit increased EZH2 expression, suggesting its role in epigenetic silencing of miRNA-338-5p/-421. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive prostate cancer cells and patients' specimens confirms epigenetic silencing., Conclusions: Our findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive prostate cancer, although restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis. See related commentary by Bjartell, p. 2679 ., (©2018 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
36. Proproliferative function of adaptor protein GRB10 in prostate carcinoma.
- Author
-
Khan MI, Al Johani A, Hamid A, Ateeq B, Manzar N, Adhami VM, Lall RK, Rath S, Sechi M, Siddiqui IA, Choudhry H, Zamzami MA, Havighurst TC, Huang W, Ntambi JM, and Mukhtar H
- Subjects
- Animals, Carcinogens antagonists & inhibitors, Carcinogens metabolism, Cell Line, Tumor, Cell Proliferation genetics, Cell Proliferation physiology, Fibroblasts cytology, Fibroblasts metabolism, GRB10 Adaptor Protein antagonists & inhibitors, GRB10 Adaptor Protein genetics, Gene Knockdown Techniques, Humans, Male, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Models, Biological, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Phosphatidylinositol 3-Kinases metabolism, Prostatic Neoplasms genetics, RNA, Messenger, Signal Transduction, GRB10 Adaptor Protein metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology
- Abstract
Growth factor receptor-binding protein 10 (GRB10) is a well-known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt-targeted therapies in prostate cancer (PCa) is loss of mTOR-regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)-deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild-type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild-type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K-driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer.-Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma.
- Published
- 2019
- Full Text
- View/download PDF
37. AKT Inhibition Modulates H3K4 Demethylase Levels in PTEN-Null Prostate Cancer.
- Author
-
Khan MI, Hamid A, Rath S, Ateeq B, Khan Q, Siddiqui IA, Adhami VM, Choudhry H, Zamzami MA, and Mukhtar H
- Subjects
- Acetylation drug effects, Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Gene Knockout Techniques, Humans, Male, Methylation drug effects, Mice, Phosphorylcholine administration & dosage, Phosphorylcholine pharmacology, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Xenograft Model Antitumor Assays, Jumonji Domain-Containing Histone Demethylases genetics, MicroRNAs genetics, Nuclear Proteins genetics, PTEN Phosphohydrolase genetics, Phosphorylcholine analogs & derivatives, Prostatic Neoplasms drug therapy, Repressor Proteins genetics
- Abstract
Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology, including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone-modulating enzymes, resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin-related events is essential. Here, we report that AKT inhibition in prostate-specific PTEN knockout mice significantly induces di- and trimethylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation-specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Furthermore, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition-mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors., (©2018 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
38. Mutagenicity and Cytotoxicity of Particulate Matter Emitted from Biodiesel-Fueled Engines.
- Author
-
Agarwal AK, Singh AP, Gupta T, Agarwal RA, Sharma N, Rajput P, Pandey SK, and Ateeq B
- Subjects
- Biofuels, Gasoline, Humans, Mutagens, Vehicle Emissions, Air Pollutants, Particulate Matter
- Abstract
Biodiesel engines produce several intermediate species, which can potentially harm the human health. The concentration of these species and their health risk potential varies depending on engine technology, fuel, and engine operating condition. In this study, experiments were performed on a large number of engines having different configurations (emissions norms/fuel used), which were operated at part load/full load using B20 (20% v/v biodiesel blended with mineral diesel) and mineral diesel. Experiments included measurement of gaseous emissions, and physical, chemical, and biological characterization of exhaust particulate matter (PM). Chemical characterization of PM was carried out for detecting polycyclic aromatic hydrocarbons (PAH's) and PM bound trace metals. The biological toxicity associated with PM was assessed using human embryonic kidney 293T cells (HEK 293T). The mutagenic potential of the PM was tested at three different concentrations (500, 100, and 50 μg/mL) using two different Salmonella strains, TA98 and TA100, with and without liver S9 metabolic enzyme fraction. PM samples exhibited cytotoxic effect on HEK 293T cells (IC
50 < 100 μg/mL) and there was significant potential for reactive oxygen species (ROS) generation. Comparison of different engines showed that modern engines (Euro-III and Euro-IV compliant) produced relatively cleaner exhaust compared to older engines (Euro-II compliant). Biodiesel-fueled engines emitted lower number of particles compared to diesel-fueled engines. However, chemical characterization revealed that biodiesel-fueled engines exhaust PM contained several harmful PAHs and trace metals, which affected the biological activity of these PM, as reflected in the biological investigations. Mutagenicity and cytotoxicity of PM from biodiesel-fueled engines were relatively higher compared to their diesel counterparts, indicating the need for exhaust gas after-treatment.- Published
- 2018
- Full Text
- View/download PDF
39. Entropically driven controlled release of paclitaxel from poly(2-ethyl-2-oxazoline) coated maghemite nanostructures for magnetically guided cancer therapy.
- Author
-
Kumar N, Tyeb S, Manzar N, Behera L, Ateeq B, and Verma V
- Subjects
- Animals, Cisplatin chemistry, Cisplatin therapeutic use, Doxorubicin chemistry, Doxorubicin therapeutic use, Drug Delivery Systems methods, Ferric Compounds chemistry, Humans, Nanostructures chemistry, Neoplasms drug therapy, Paclitaxel chemistry, Paclitaxel therapeutic use, Polyamines chemistry, Polymers chemistry
- Abstract
Theranostic nanostructures serve a dual purpose of therapy and diagnosis. A major fraction of these are based on polymer coated magnetic nanostructures of iron oxides (magnetite and maghemite), owing to the efficient drug loading capacity of polymer shells and enhanced magnetic contrast effects of the iron oxide core. In the current work we are proposing poly(2-ethyl-2-oxazoline) coated linear thermoresponsive nanostructures of maghemite (γ-Fe
2 O3 ) for potential application in targeted cancer therapy. The polymer coating was obtained via a modified sol-gel technique based on entropically driven phase separation of poly(2-ethyl-2-oxazoline) above its cloud point (CP) temperature of 63 °C in water. The developed nanostructures were further loaded with paclitaxel, a polar anticancer compound at room temperature (25 °C). The entropically driven release of paclitaxel at various concentrations and physiological temperatures was modeled and their application to the PC3 prostrate cancer cell line was investigated by treating in vitro. The steering efficiency of the magnetic nanostructures during their navigation through large blood vessels was also analyzed with the help of a synthetic model of the human axillary artery. The proposed application of these newly developed nanostructures can easily be extended towards localized delivery of additional polar anticancer drugs like cisplatin and doxorubicin.- Published
- 2018
- Full Text
- View/download PDF
40. Toxicity and mutagenicity of exhaust from compressed natural gas: Could this be a clean solution for megacities with mixed-traffic conditions?
- Author
-
Agarwal AK, Ateeq B, Gupta T, Singh AP, Pandey SK, Sharma N, Agarwal RA, Gupta NK, Sharma H, Jain A, and Shukla PC
- Subjects
- Air Pollutants analysis, Cities, Gasoline analysis, Motor Vehicles, Mutagenicity Tests, Mutagens, Polycyclic Aromatic Hydrocarbons analysis, Salmonella, Vehicle Emissions analysis, Air Pollutants toxicity, Natural Gas toxicity, Toxicity Tests, Vehicle Emissions toxicity
- Abstract
Despite intensive research carried out on particulates, correlation between engine-out particulate emissions and adverse health effects is not well understood yet. Particulate emissions hold enormous significance for mega-cities like Delhi that have immense traffic diversity. Entire public transportation system involving taxis, three-wheelers, and buses has been switched from conventional liquid fuels to compressed natural gas (CNG) in the Mega-city of Delhi. In this study, the particulate characterization was carried out on variety of engines including three diesel engines complying with Euro-II, Euro-III and Euro-IV emission norms, one Euro-II gasoline engine and one Euro-IV CNG engine. Physical, chemical and biological characterizations of particulates were performed to assess the particulate toxicity. The mutagenic potential of particulate samples was investigated at different concentrations using two different Salmonella strains, TA98 and TA100 in presence and absence of liver S9 metabolic enzyme fraction. Particulates emitted from diesel and gasoline engines showed higher mutagenicity, while those from CNG engine showed negligible mutagenicity compared to other test fuels and engine configurations. Polycyclic aromatic hydrocarbons (PAHs) adsorbed onto CNG engine particulates were also relatively fewer compared to those from equivalent diesel and gasoline engines. Taken together, our findings indicate that CNG is comparatively safer fuel compared to diesel and gasoline and can offer a cleaner transport energy solution for mega-cities with mixed-traffic conditions, especially in developing countries., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
41. Association of AGTR1 (A1166C) and ACE (I/D) Polymorphisms with Breast Cancer Risk in North Indian Population.
- Author
-
Singh A, Srivastava N, Amit S, Prasad SN, Misra MP, and Ateeq B
- Abstract
Renin angiotensin system (RAS) comprising Angiotensin converting enzyme (ACE), Angiotensin II (Ang II) and its receptor Angiotensin II receptor type I (AGTR1), plays a critical role in several diseases including cancer. A single nucleotide polymorphism (SNP) A1166C located in 3' untranslated region (UTR) of AGTR1 and an insertion/deletion (I/D) polymorphism present in intron 16 of ACE gene have been associated with many diseases, but their association with Breast cancer (BCa) is still debatable. Here, we for the first time investigated the association of these polymorphisms in a North Indian BCa cohort including 161 patients and 152 healthy women. The polymorphisms were evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) respectively. The association between these polymorphisms and BCa risk was estimated by calculating Odds Ratio (OR) and chi-square (χ
2 ) test. The DD genotype/D allele of ACE (I/D) polymorphism and "AC and CC" genotype/C allele of AGTR1 (A1166C) polymorphism were associated with higher risk of BCa when evaluated independently. Furthermore, interaction analysis of "AC and CC" and DD genotype and combination of "C and D" alleles of both polymorphisms revealed significantly greater BCa risk than that observed independently. Conclusively, women harboring "AC or CC" genotype/C allele for AGTR1 (A1166C) polymorphism and DD genotype/D allele for ACE (I/D) polymorphisms have a predisposition to develop more aggressive disease with advanced staging and larger tumor size. Our study indicates importance of genetic screening based on these polymorphisms for women, who may have higher risk of BCa., (Copyright © 2017 Oncoinvent AS. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
42. Direct Intranuclear Anticancer Drug Delivery via Polydimethylsiloxane Nanoparticles: in Vitro and in Vivo Xenograft Studies.
- Author
-
Mishra G, Bhattacharyya S, Bhatia V, Ateeq B, Sharma A, and Sivakumar S
- Subjects
- Animals, Antineoplastic Agents, Cell Line, Tumor, Dimethylpolysiloxanes, Doxorubicin, Drug Carriers, Drug Delivery Systems, Heterografts, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Nanoparticles
- Abstract
Direct delivery of anticancer drugs to nuclei of tumor cells is required to enhance the therapeutic activity, which can be achieved by a nuclear localization signal (NLS) or peptide-decorated nanovehicles. However, NLS/peptide-based approaches may create certain undesirable immunological responses and the utilized synthesis processes are generally labor intensive. To this end, we report ligand-free, enhanced intranuclear delivery of Doxorubicin (Dox) to different cancer cells via porous polydimethylsiloxane (PDMS) nanoparticles (NPs). PDMS NPs were prepared by sacrificial silica template-based approach and Dox was loaded into the pores of PDMS NPs. These Dox-loaded PDMS NPs show enhanced cytotoxicity and reduce the IC50 values by 84 and 54% for HeLa and PC-3, respectively, compared to free Dox. Further, DNA damage in HeLa cells was estimated using comet assay suggesting enhanced DNA damage (72%) with Dox-loaded PDMS NPs as compared to free Dox (12%). The therapeutic efficiency of PDMS-Dox drug delivery system was tested in prostate cancer (PC-3) xenografts in NOD/SCID mice which showed enhanced tumor reduction (∼66%) as compared to free Dox. Taken together, our PDMS-Dox delivery system shows efficient and enhanced transportation of Dox to tumor cells which can be harnessed to develop advanced chemotherapy-based approaches to treat prostate and other cancers.
- Published
- 2017
- Full Text
- View/download PDF
43. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer.
- Author
-
Wang X, Qiao Y, Asangani IA, Ateeq B, Poliakov A, Cieślik M, Pitchiaya S, Chakravarthi BVSK, Cao X, Jing X, Wang CX, Apel IJ, Wang R, Tien JC, Juckette KM, Yan W, Jiang H, Wang S, Varambally S, and Chinnaiyan AM
- Published
- 2017
- Full Text
- View/download PDF
44. Targeting NF-kappa B Signaling by Artesunate Restores Sensitivity of Castrate-Resistant Prostate Cancer Cells to Antiandrogens.
- Author
-
Nunes JJ, Pandey SK, Yadav A, Goel S, and Ateeq B
- Subjects
- Animals, Apoptosis drug effects, Artesunate, Caspase 3 metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Humans, Male, Mice, Neoplasm Metastasis, Oxidative Stress, Phosphorylation, Poly(ADP-ribose) Polymerases metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology, Proteolysis, Tumor Burden, Ubiquitin metabolism, Xenograft Model Antitumor Assays, Androgen Receptor Antagonists pharmacology, Antineoplastic Agents pharmacology, Artemisinins pharmacology, Drug Resistance, Neoplasm, NF-kappa B metabolism, Prostatic Neoplasms, Castration-Resistant metabolism, Signal Transduction drug effects
- Abstract
Androgen deprivation therapy (ADT) is the most preferred treatment for men with metastatic prostate cancer (PCa). However, the disease eventually progresses and develops resistance to ADT in majority of the patients, leading to the emergence of metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed artesunate (AS), an artemisinin derivative, for its anticancer properties and ability to alleviate resistance to androgen receptor (AR) antagonists. We have shown AS in combination with bicalutamide (Bic) attenuates the oncogenic properties of the castrate-resistant (PC3, 22RV1) and androgen-responsive (LNCaP) PCa cells. Mechanistically, AS and Bic combination inhibits nuclear factor (NF)-κB signaling and decreases AR and/or AR-variant 7 expression via ubiquitin-mediated proteasomal degradation. The combination induces oxidative stress and apoptosis via survivin downregulation and caspase-3 activation, resulting in poly-ADP-ribose polymerase (PARP) cleavage. Moreover, preclinical castrate-resistant PC3 xenograft studies in NOD/SCID mice (n =28, seven per group) show remarkable tumor regression and significant reduction in lungs and bone metastases upon administering AS (50 mg/kg per day in two divided doses) and Bic (50 mg/kg per day) via oral gavage. Taken together, we for the first time provide a compelling preclinical rationale that AS could disrupt AR antagonist-mediated resistance observed in mCRPC. The current study also indicates that the therapeutic combination of Food and Drug Administration-approved AS or NF-κB inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC patients., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
45. Ag/AgO Nanoparticles Grown via Time Dependent Double Mechanism in a 2D Layered Ni-PCP and Their Antibacterial Efficacy.
- Author
-
Agarwal RA, Gupta NK, Singh R, Nigam S, and Ateeq B
- Subjects
- Escherichia coli drug effects, Microbial Sensitivity Tests, Microscopy, Atomic Force, Models, Molecular, Molecular Conformation, Particle Size, X-Ray Diffraction, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Metal Nanoparticles chemistry, Metal Nanoparticles ultrastructure, Metal-Organic Frameworks chemistry, Metal-Organic Frameworks pharmacology, Metal-Organic Frameworks ultrastructure, Nickel chemistry, Oxides chemistry, Oxides pharmacology, Silver chemistry, Silver pharmacology, Silver Compounds chemistry, Silver Compounds pharmacology
- Abstract
A simple synthesis route for growth of Ag/AgO nanoparticles (NPs) in large quantitative yields with narrow size distribution from a functional, non-activated, Ni (II) based highly flexible porous coordination polymer (PCP) as a template has been demonstrated. This template is a stable storage media for the NPs larger than the pore diameters of the PCP. From EPR study it was concluded that NPs were synthesized via two mechanisms i.e. acid formation and the redox activity of the framework. Size range of Ag/AgO NPs is sensitive to choice of solvent and reaction time. Direct use of Ag/AgO@Ni-PCP shows influential growth inhibition towards Escherichia coli and the pathogen Salmonella typhimurium at extremely low concentrations. The pristine template shows no cytotoxic activity, even though it contains Ni nodes in the framework.
- Published
- 2017
- Full Text
- View/download PDF
46. Molecular Discriminators of Racial Disparities in Prostate Cancer.
- Author
-
Ateeq B, Bhatia V, and Goel S
- Subjects
- Ethnicity, Genetic Predisposition to Disease, Humans, Male, Racial Groups, Serine Endopeptidases genetics, Transcriptional Regulator ERG genetics, Trypsin Inhibitor, Kazal Pancreatic genetics, Prostatic Neoplasms ethnology, Prostatic Neoplasms genetics
- Abstract
Recent molecular characterization of prostate cancer (PCa) identified novel genetic aberrations and disease subtypes. The frequencies of molecular aberrations show racial disparity. Clinical strategies and targeted therapies embracing these racial differences are required. Here we discuss ethnic differences in genetic alterations and their impact on the susceptibility, progression, and treatment of prostate cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
47. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases.
- Author
-
Singh A, Nunes JJ, and Ateeq B
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms metabolism, Humans, Molecular Targeted Therapy, Neoplasm Metastasis, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Disease Progression, Receptors, G-Protein-Coupled metabolism
- Abstract
G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
48. Molecular profiling of ETS and non-ETS aberrations in prostate cancer patients from northern India.
- Author
-
Ateeq B, Kunju LP, Carskadon SL, Pandey SK, Singh G, Pradeep I, Tandon V, Singhai A, Goel A, Amit S, Agarwal A, Dinda AK, Seth A, Tsodikov A, Chinnaiyan AM, and Palanisamy N
- Subjects
- Carrier Proteins genetics, Gene Deletion, Gene Expression, Gene Expression Profiling, Gene Rearrangement genetics, Humans, Immunohistochemistry, In Situ Hybridization, In Situ Hybridization, Fluorescence, India, Male, PTEN Phosphohydrolase, Prognosis, Trans-Activators genetics, Transcriptional Regulator ERG, Trypsin Inhibitor, Kazal Pancreatic, raf Kinases genetics, Prostatic Neoplasms genetics, Proto-Oncogene Proteins c-ets genetics
- Abstract
Background: Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort., Methods: In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH)., Results: ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over-expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG-positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively., Conclusions: This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over-expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision-making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention., (© 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
49. Identification of targetable FGFR gene fusions in diverse cancers.
- Author
-
Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, and Chinnaiyan AM
- Subjects
- Animals, Gene Fusion, Gene Knockdown Techniques, Gene Rearrangement, High-Throughput Screening Assays, Humans, Male, Mice, Mice, SCID, Molecular Targeted Therapy, Neoplasms metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Prospective Studies, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction, Xenograft Model Antitumor Assays, Neoplasms drug therapy, Neoplasms genetics, Receptors, Fibroblast Growth Factor genetics
- Abstract
Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.
- Published
- 2013
- Full Text
- View/download PDF
50. The role of sarcosine metabolism in prostate cancer progression.
- Author
-
Khan AP, Rajendiran TM, Ateeq B, Asangani IA, Athanikar JN, Yocum AK, Mehra R, Siddiqui J, Palapattu G, Wei JT, Michailidis G, Sreekumar A, and Chinnaiyan AM
- Subjects
- Aged, Animals, Case-Control Studies, Cell Line, Tumor, Disease Progression, Gene Expression, Gene Expression Regulation, Neoplastic, Glycine N-Methyltransferase genetics, Glycine N-Methyltransferase metabolism, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Neoplasm Invasiveness, Neoplasm Transplantation, Prostatic Neoplasms enzymology, Prostatic Neoplasms pathology, Sarcosine Dehydrogenase genetics, Sarcosine Dehydrogenase metabolism, Sarcosine Oxidase genetics, Sarcosine Oxidase metabolism, Tumor Burden, Biomarkers, Tumor urine, Prostatic Neoplasms urine, Sarcosine urine
- Abstract
Metabolomic profiling of prostate cancer (PCa) progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic PCa and modest but significant elevation of the metabolite in PCa urine. Here, we examine the role of key enzymes associated with sarcosine metabolism in PCa progression. Consistent with our earlier report, sarcosine levels were significantly elevated in PCa urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71. In addition, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in PCa tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Accordingly, addition of sarcosine, but not glycine or alanine, induced invasion and intravasation in an in vivo PCa model. In contrast, GNMT knockdown or SARDH overexpression in PCa xenografts inhibited tumor growth. Taken together, these studies substantiate the role of sarcosine in PCa progression.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.