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EGFL6, a growth factor produced by adipocytes, is upregulated in and implicated in the tumorigenesis of multiple tumor types. Given the strong link between obesity and endometrial cancer, we sought to determine the impact of EGFL6 on endometrial cancer. EGFL6 expression in endometrial cancer and correlation with patient outcomes was evaluated in the human protein atlas and TCGA. EGFL6 treatment, expression upregulation, and shRNA knockdown were used to evaluate the impact of EGFL6 on the proliferation and migration of 3 endometrial cancer cell lines in vitro. Similarly, the impact of EGFL6 expression and knockdown on tumor growth was evaluated. Western blotting was used to evaluate the impact of EGFL6 on MAPK phosphorylation. EGFL6 is upregulated in endometrial cancer, primarily in cony-number high tumors. High tumor endometrial cancer expression of EGFL6 predicts poor patient prognosis. We find that EGFL6 acts to activate the MAPK pathway increasing cellular proliferation and migration. In xenograft models, EGFL6 overexpression increases endometrial cancer tumor growth while EGFL6 knockdown decreases endometrial cancer tumor growth. EGFL6 is a marker of poor prognosis endometrial cancers, driving cancer cell proliferation and growth. As such EGFL6 represents a potential therapeutic target in endometrial cancer. • EGFL6 is upregulated in endometrial cancer, primarily in copy-number high tumors. • EGFL6 upregulation in endometrial cancer portends poor prognosis. • EGFL6 increases endometrial cancer cell proliferation and migration. • Loss of EGFL6 significantly restricts endometrial cancer growth. • EGFL6 represents a potential therapeutic target for poor prognosis endometrial cancer. [ABSTRACT FROM AUTHOR]

Studies have shown that the high expression of EphA4 in gastric cancer tissues may correlate with unfavorable clinical pathological characteristics. Therefore, EphA4 may be an effective target for treating gastric cancer in addition to HER-2/neu. In this study, generated scFv S3 can bind endogenous EphA4 of gastric cancer cells and has significant membrane staining. Additionally, scFv S3 binding to EphA4 inhibits the growth and migration of cancer cells and the growth induction that ephrinA1 generates in gastric cancer cells. We found that EphA4 molecules may degrade through antibody treatment of cells, and the increase in LAMP1 and LAMP2 indicates that lysosome is involved in the degradation. The scFv S3 administration leads to the signals pAKT, pERK, and pSTAT3 decrease in cancer cells. The xenograft model of HER-2/neu low expressing gastric cancer cell SNU-16 exhibits better therapeutic effects by scFv S3 than trastuzumab scFv. The scFv S3 administration in vivo can degrade EphA4 molecules in tumor tissues, decreasing Ki67 and increasing cleaved C3 molecule expression. Furthermore, we identified and validated that scFv S3 generates essential ionic bonding with R162 on EphA4. The antibody may provide effective treatment for patients with gastric cancer and abnormal activation or overexpression of EphA4 signaling. • EphA4 may be an effective target for the clinical treatment of gastric cancer. • The anti-EphA4 antibodies have neutralizing effects against gastric tumor growth. • The R162 on EphA4 is the key residue that affected the antibody response. [ABSTRACT FROM AUTHOR]

One-carbon metabolism is essential for our human cells to carry out nucleotide synthesis, methylation, and reductive metabolism through one-carbon units, and these pathways ensure the high proliferation rate of cancer cells. Serine hydroxymethyltransferase 2 (SHMT2) is a key enzyme in one-carbon metabolism. This enzyme can convert serine into a one-carbon unit bound to tetrahydrofolate and glycine, ultimately supporting the synthesis of thymidine and purines and promoting the growth of cancer cells. Due to SHMT2's crucial role in the one-carbon cycle, it is ubiquitous in human cells and even in all organisms and highly conserved. Here, we summarize the impact of SHMT2 on the progression of various cancers to highlight its potential use in the development of cancer treatments. • SHMT2 is a relatively novel research goal in recent years. • SHMT2 is a key enzyme in one-carbon metabolism. • SHMT2 potential use in the development of cancer treatments. • This study aims to understand the progression of various cancers and explore long-term treatment options. [ABSTRACT FROM AUTHOR]

[Display omitted] Nucleus targeting is tremendously important in cancer therapy. Cationic carbon dots (CCDs) are potential nanoparticles which might enter cells and penetrate nuclear membranes. Although some CCDs have been investigated in nucleus targeting and applied in nuclear imaging, the CCDs derived from drugs, that are able to target the nucleus, bind with DNA and inhibit the growth of cancer cells have not been reported. In this project, 1, 2, 4, 5-benzenetetramine (Y15, a focal adhesion kinase inhibitor) derived cationic carbon dots (Y15-CDs) were prepared via a hydrothermal approach utilizing Y15, folic acid and 1,2-ethylenediamine as precursors. Based on the structural, optical, and morphologic characterizations, Y15-CDs possess rich amine groups and nitrogen in structure, an excitation-dependent photoluminescence emission, and a small particle size of 2 to 4 nm. The DNA binding experiments conducted through agarose gel electrophoresis, UV–vis absorption, fluorescence emission, and circular dichroism spectroscopies, prove that Y15-CDs might bind with DNA via electrostatic interactions and partially intercalative binding modes. In addition, the cell imaging and cytotoxicity studies in human foreskin fibroblasts (HFF), prostate cancer (PC3) and osteosarcoma cells (U2OS) indicate the nucleus targeting and anticancer abilities of Y15-CDs. Most interestingly, Y15-CDs exhibit a higher cytotoxicity to cancer cells (PC3 and U2OS) than to normal cells (HFF), inferring that Y15-CDs might be potentially applied in cancer therapy. [ABSTRACT FROM AUTHOR]

• CXCL2 expression increases in Schwann cells activated by breast cancer cells. • Perineural breast cancer cell implantation results in mechanical hypersensitivity. • Breast cancer cells promote CXCL2 secretion of Schwann cells through Ref-1 pathway. Pain is one of the most severe complications affecting the quality of life of cancer patients. Although substantial progress has been made in the diagnosis and treatment of cancer, the neurobiological mechanism of cancer pain is still unclear. In the present study, we identified the critical role of CXC chemokine 2 (CXCL2), released by Schwann cells after being activated by cancer cells, in maintaining cancer-induced macrophage infiltration and the resulting mechanical hypersensitivity and persistent spontaneous nociception. In vitro , Schwann cells cocultured with breast cancer cells exhibited a significant increase in CXCL2 expression; in addition, conditioned medium from Schwann cells activated by breast cancer cells had a similar effect to recombinant CXCL2 in terms of inducing macrophage migration. Targeting CXCL2 signaling by both CXC chemokine receptor 2 (CXCR2) antagonist pharmacological blockade and anti-CXCL2 mAb immunological blockade robustly prevented conditioned medium-induced macrophage migration. In vivo , both application of recombinant CXCL2 and perineural breast cancer cell implantation resulted in mechanical hypersensitivity and persistent spontaneous nociception in mice, along with increased macrophage infiltration into the sciatic nerves. Similar to the in vitro results, inhibition of CXCL2/CXCR2 signaling or conditional knockdown of CXCL2 in sciatic nerve Schwann cells effectively attenuated breast cancer cell-induced mechanical hypersensitivity, persistent spontaneous nociception, and macrophage recruitment in the sciatic nerve. Mechanistically, we found that redox effector factor-1 (Ref-1) secreted by breast cancer cells activated hypoxia inducible factor-1α (HIF-1α) expression and inhibited reactive oxygen species (ROS) production in Schwann cells, ultimately inducing CXCL2 expression in Schwann cells. In brief, the present study expands new insights into cancer pain mechanisms from promising animal models to provide new strategies for the control of cancer pain. [ABSTRACT FROM AUTHOR]

Nucleus accumbens-associated 1 (NAC1) is a member of pox virus and zinc finger/bric-a-brac tramtrack broad complex (BTB/POZ) gene family. Overexpression of NAC1 is implicated in cancer development, recurrence and chemotherapy resistance. In our previous study, we found NAC1 was a potential small ubiquitin-like modifier (SUMO) substrate in prostate cancer cells. However, there was still lack of evidences to further support and validate the result. In this work, we found that NAC1 is a multi-SUMO-sites acceptor. The SUMO acceptor lysines were K167, K318, K368, K483 and K498. SUMOylation didn't alter the localization of NAC1, but facilitated the formation of NAC1 nuclear bodies. Compared with NAC1 wild type (NAC1 WT), the SUMO-sites mutant of NAC1 (NAC1 SM) suppressed cell proliferation and tumor growth in cellular and animal levels. This work uncovered the function of SUMOylation of NAC1 in prostate cancer cells. • NAC1 is a multi-SUMO-sites acceptor. • The SUMOylation of NAC1 facilitates the formation of NAC1 nuclear bodies. • The SUMOylation of NAC1 affects the growth of prostate cancer cells. [ABSTRACT FROM AUTHOR]

Cervical cancer is one of the most lethal gynaecological malignancies in females. The deubiquitylase UCHL3 has been studied as an oncogenic factor in multiple cancers. However, the expression pattern and function profile of UCHL3 in cervical cancer hasn't been fully characterized. Here, we revealed that UCHL3 was highly expressed in cervical cancer and overexpressed UCHL3 predicted a poor survival probability in cervical cancer patients. Our findings showed that knockdown of UCHL3 inhibited cell growth, migration and invasion in cervical cancer cells while UCHL3 knockdown inhibited cervical cancer development and metastasis in vivo in mouse models. Mechanistically, co-immunoprecipitation assay showed that UCHL3 directly interacted with NRF2. Knockdown of UCHL3 decreased NRF2 expression while overexpression of UCHL3 stabilized NRF2 via deubiquitination. In addition, overexpression of UCHL3 with C92A mutation didn't affect NRF2 stability. Moreover, we revealed that overexpression of NRF2 could antagonize the function of UCHL3 knockdown in cervical cancer cells. Collectively, our findings suggest that UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination. Thus, UCHL3/NRF2 axis could be utilized to develop efficient treatments for cervical cancer patients. • UCHL3 is highly expressed in cervical cancer and predicts poor survival. • Knockdown of UCHL3 suppresses cervical cancer cell growth and invasion. • UCHL3 interacts with NRF2 and stabilizes NRF2 via deubiquitination. [ABSTRACT FROM AUTHOR]

Breast cancer is malignant cancer that severely threatens the life quality of female patients. N6-methyladenosine (m6A) is a prevalent modification of RNA. METTL16 is an important methyltransferase. This work aims to study the role of METTL16 in breast cancer cell death. The expression of METTL16 in clinical breast cancer specimens was analyzed by qPCR assay. The in vitro and in vivo breast cancer cell proliferation was measured by CCK8, colony formation, and xenograft mouse model. Cell ferroptosis was assessed by measuring the accumulation of iron, Fe2+, and lipid ROS. The mechanistic study was performed by RNA degradation, qPCR, and Western blotting assay. METTL16 was overexpressed in tumor tissues from breast cancer patients compared with the para-tumor tissues. Knockdown of METTL16 suppressed in vitro cell proliferation and in vivo tumor growth of breast cancer cells. Meanwhile, METTL16 silencing led to elevated intracellular levels of iron, Fe2+, and lipid ROS, indicating the incidence of ferroptosis. Furthermore, siMETTL16 decreased m6A methylation and enhanced the degradation of GPX4 RNA. METTL16-regulated m6A methylation of GPX4 stimulates proliferation and suppresses ferroptosis of breast cancer cells. Therefore, we concluded that METTL16 epigenetically enhanced GPX4 expression via m6A modification to promote breast cancer progression by inhibiting ferroptosis. • METTL16 is upregulated in breast cancer and promote cancer cell growth. • Silencing of METTL16 triggers breast cancer cell ferroptosis. • Silencing of METTL16 inhibits breast cancer growth in vivo. • METTL16 modulates breast cancer cell ferroptosis via m6A modification of GPX4. • Overexpression of GPX4 abolishes METTL16 depletion-induced ferroptosis. [ABSTRACT FROM AUTHOR]

This study aimed to determine the role of COL17A1 in tumor progression and predict the prognosis of pancreatic cancer (PC). RNA-seq data from The Cancer Genome Atlas and Genotype-Tissue Expression were analyzed using bioinformatics methods. "Limma" package was used to screen differentially expressed genes (DEGs). Prognostic-associated data were further analyzed using univariate Cox regression and verified using the GSE28375 and GSE62452 datasets. Protein-protein interaction (PPI) network analysis was integrated to screen for hub genes. In vitro quantitative real-time PCR (qPCR) and western blotting were used to detect gene expression. The functional attributes of PC cells were verified by wound healing assays, migration and invasion assays, Cell Counting Kit 8 (CCK8), and 5-ethynyl-2′-deoxyuridine (EdU) assay. On analyzing PC data, 4637 DEGs were identified. Of these, 2399 genes were upregulated and 2238 were downregulated. Through PPI network analysis, we identified that COL17A1 expression was highly correlated with poor prognosis of patients with PC. Functional attribute assays in the in vitro study showed that COL17A1 knockdown inhibited PC cell proliferation, migration, and invasion. According to our results, COL17A1 promotes PC cell proliferation, migration, and invasion mediated by the epithelial-mesenchymal transition (EMT) pathway. Thus, COL17A1 could be used as a prognostic marker in PC. • COL17A1 has higher expression levels in pancreatic cancer tissue than normal pancreatic tissue. • COL17A1 significantly promotes pancreatic cancer cells growth, migration and invasion via regulating EMT pathways. • COL17A1 is a valuable indicator to assess prognosis, and providedes a promising therapeutic target for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Anti-diabetic drug, metformin, has attracted attentions as an anti-cancer agent due to the suppression of mTORC1 as a master switch of cell growth in various cancers. Upon mTORC1 inhibition, translation of proteins possessing IRES elements in their mRNAs still occurs in order to maintain proper cell function. Thus, inhibitor of apoptosis proteins are expected to be upregulated by mTORC1 inhibition due to the possession of IRES elements. Surprisingly, however, inhibition of mTORC1 with metformin in breast cancer cell lines of MDA-MB-231 and MCF-7, caused the downregulation of IRES-element possessing proteins of cIAP1, XIAP and Bcl-2, 24 h post-treatment. Interestingly, a shorter treatment time of 8 h, however, was accompanied by increased expression of these proteins. Importantly, inclusion of the proteasome inhibitor, Bortezomib, caused the upregulation of the tested anti-apoptotic proteins in both cell lines. These observations suggest that mTORC1 inhibition has a bifold effect; first upregulation of IRES-dependent survival proteins to prevent untimely cell death followed by an opposite effect, which is the enhanced proteosomal degradation of these protein in order to maintain a balanced response. • Metformin mediated mTORC1 inhibition enhances IRES-dependent translation of antiapoptotic proteins. • This effect on ani-apoptotic proteins is countered by enhanced proteosomal degradation, also mediated by mTORC1 inhibition. • mTORC1 inhibition upregulated anti-apoptotic proteins to prevent untimely cell death. • Proteasome constantly degrades anti apoptosis proteins to keep a balanced response. [ABSTRACT FROM AUTHOR]

Brain cancer is an aggressive type of cancer with poor prognosis. While the immune system protects against cancer in the early stages, the tumor exploits the healing arm of inflammatory reactions to accelerate its growth and spread. Various immune cells penetrate the developing tumor region, establishing a pro-inflammatory tumor milieu. Additionally, tumor cells may release chemokines and cytokines to attract immune cells and promote cancer growth. Inflammation and its associated mechanisms in the progression of cancer have been extensively studied in the majority of solid tumors, especially brain tumors. However, treatment of the malignant brain cancer is hindered by several obstacles, such as the blood-brain barrier, transportation inside the brain interstitium, inflammatory mediators that promote tumor growth and invasiveness, complications in administering therapies to tumor cells specifically, the highly invasive nature of gliomas, and the resistance to drugs. To resolve these obstacles, nanomedicine could be a potential strategy that has facilitated advancements in diagnosing and treating brain cancer. Due to the numerous benefits provided by their small size and other features, nanoparticles have been a prominent focus of research in the drug-delivery field. The purpose of this article is to discuss the role of inflammatory mediators and signaling pathways in brain cancer as well as the recent advances in understanding the nano-carrier approaches for enhancing drug delivery to the brain in the treatment of brain cancer. [ABSTRACT FROM AUTHOR]

Several metabolic pathways for the supply of adenosine triphosphate (ATP) have been proposed; however, the major source of reducing power for ADP in cancer remains unclear. Although glycolysis is the source of ATP in tumors according to the Warburg effect, ATP levels do not differ between cancer cells grown in the presence and absence of glucose. Several theories have been proposed to explain the supply of ATP in cancer, including metabolic reprograming in the tumor microenvironment. However, these theories are based on the production of ATP by the TCA-OxPhos pathway, which is inconsistent with the Warburg effect. We found that blocking fatty acid oxidation (FAO) in the presence of glucose significantly decreased ATP production in various cancer cells. This suggests that cancer cells depend on fatty acids to produce ATP through FAO instead of glycolysis. We observed that cancer cell growth mainly relies on metabolic nutrients and oxygen systemically supplied through the bloodstream instead of metabolic reprogramming. In a spontaneous mouse tumor model (Kras G12D ; Pdx1-cre), tumor growth was 2-fold higher in mice fed a high-fat diet (low-carbo diet) that caused obesity, whereas a calorie-balanced, low-fat diet (high-carbo diet) inhibited tumor growth by 3-fold compared with that in mice fed a control/normal diet. This 5-fold difference in tumor growth between mice fed low-fat and high-fat diets suggests that fat-induced obesity promotes cancer growth, and tumor growth depends on fatty acids as the primary source of energy. [Display omitted] • All living cells produce ATP in mitochondria using the TCA cycle or fatty acid oxidation (FAO). • However, cancer cells do not use carbohydrates for the TCA cycle because of the Warburg effect. • Therefore, cancer cells must rely on OxPhos with the ETC using fatty acids supplied from blood vessels to produce ATP. [ABSTRACT FROM AUTHOR]

Gastric cancer is a one of the most common malignant tumors with poor prognosis worldwide. Leucine-rich G-protein-coupled receptor 5 (LGR5) is determined as a modulator of Wnt signaling cascade and R-spondins are a family of secretory agonists in the Wnt signaling and act as ligands to interact with LGR5. However, the function of Rspondin-1 in GC remains obscure. Here, we identified the effect of Rspondin-1 on GC progression. Rspondin-1 and LGR5 were upregulated in clinical gastric cancer tissues. CCK-8 assay revealed that the viability of GC cells was reduced by Rspondin-1 depletion and enhanced by Rspondin-1 overexpression. The depletion of Rspondin-1 decreased while the overexpression of Rspondin-1 increased the numbers of colony formation and Edu-positive GC cells. The depletion of Rspondin-1 attenuated the invasion and migration ability of GC cells. Moreover, sphere formation assays revealed that the knockdown of Rspondin-1 reduced the stemness of GC cells. The expression of cancer stem cell markers, including Nanog, OCT3/4, and SOX2 were suppressed by Rspondin-1 depletion in GC cells. Rspondin-1 induced tumor growth of gastric cancer cells in vivo. Mechanically, the cell viability and invasion suppressed by the depletion of Rspondin-1 in GC cells were rescued by LGR5 overexpression. Besides, the overexpression of LGR5 reversed Rspondin-1 knockdown-inhibited Nanog and OCT3/4 expression. Consequently, we concluded that Rspondin-1 contributes to the progression and stemness of gastric cancer by LGR5. • Rspondin-1 and LGR5 are upregulated in clinical gastric cancer tissues. • Rspondin-1 contributes to proliferation of gastric cancer cells in vitro. • Rspondin-1 promotes migration and invasion of gastric cancer cells in vitro. • Rspondin-1 enhances cancer stem cell properties of gastric cancer cells in vitro. • Rspondin-1 induces tumor growth of gastric cancer cells in vivo • Rspondin-1 contributes to progression of gastric cancer by LGR5. [ABSTRACT FROM AUTHOR]

Ribonucleotide reductase (RNR) is a multi-subunit enzyme responsible for catalyzing the rate-limiting step in the production of deoxyribonucleotides essential for DNA synthesis and repair. The active RNR complex is composed of multimeric R1 and R2 subunits. The RNR catalysis involves the formation of tyrosyl radicals in R2 subunits and thiyl radicals in R1 subunits. Despite the quaternary structure and cofactor diversity, all the three classes of RNR have a conserved cysteine residue at the active site which is converted into a thiyl radical that initiates the substrate turnover, suggesting that the catalytic mechanism is somewhat similar for all three classes of the RNR enzyme. Increased RNR activity has been associated with malignant transformation, cancer cell growth, and tumorigenesis. Efforts concerning the understanding of RNR inhibition in designing potent RNR inhibitors/drugs as well as developing novel approaches for antibacterial, antiviral treatments, and cancer therapeutics with improved radiosensitization have been made in clinical research. This review highlights the precise and potent roles of NO in RNR inhibition by targeting both the subunits. Under nitrosative stress, the thiols of the R1 subunits have been found to be modified by S-nitrosylation and the tyrosyl radicals of the R2 subunits have been modified by nitration. In view of the recent advances and progresses in the field of nitrosative modifications and its fundamental role in signaling with implications in health and diseases, the present article focuses on the regulations of RNR activity by S-nitrosylation of thiols (R1 subunits) and nitration of tyrosyl residues (R2 subunits) which will further help in designing new drugs and therapies. • Increased Ribonucleotide reductase (RNR) activity has been associated with malignant transformation, cancer cell growth, and tumorigenesis. • Efforts concerning the understanding of RNR inhibition in designing potent RNR inhibitors/drugs as well as developing novel approaches for antibacterial, antiviral treatments, and cancer therapeutics with improved radiosensitization have been made in clinical research. • Under nitrosative stress, the thiols of the R1 subunits have been found to be modified by S-nitrosylation and the tyrosyl radicals of the R2 subunits have been modified by nitration. • The present article focuses on the regulations of RNR activity by S-nitrosylation of thiols (R1 subunits) and nitration of tyrosyl residues (R2 subunits) which will further help in developing design new drugs and therapies. [ABSTRACT FROM AUTHOR]

Casein kinase 1α (CK1α) is a serine/threonine protein kinase that acts in various cellular processes affecting cell division and signal transduction. CK1α is present as multiple splice variants that are distinguished by the presence or absence of a long insert (L-insert) and a short carboxyl-terminal insert (S-insert). When overexpressed, zebrafish CK1α splice variants exhibit different biological properties, such as subcellular localization and catalytic activity. However, whether endogenous, alternatively spliced CK1α gene products also differ in their biological functions has yet to be elucidated. Here, we identify a panel of splice variant specific CK1α antibodies and use them to show that four CK1α splice variants are expressed in mammals. We subsequently show that the relative abundance of CK1α splice variants varies across distinct mouse tissues and between various cancer cell lines. Furthermore, we identify pathways whose expression is noticeably altered in cell lines enriched with select splice variants of CK1α. Finally, we show that the S-insert of CK1α promotes the growth of HCT 116 cells as cells engineered to lack the S-insert display decreased cell growth. Together, we provide tools and methods to identify individual CK1α splice variants, which we use to begin to uncover the differential biological properties driven by specific splice variants of mammalian CK1α. • CK1α splice variant abundance varies across normal tissues and cancer cell lines. • Cancer cell lines with high levels of select CK1α splice variants express distinct biological pathways. • The S-insert of CK1α promotes cell growth in a cancer cell line. [ABSTRACT FROM AUTHOR]

The role of extracellular matrix (ECM) prevalent in the brain metastatic breast cancer (BMBC) niche in mediating cancer cell growth, survival, and response to therapeutic agents is not well understood. Emerging evidence suggests a vital role of ECM of the primary breast tumor microenvironment (TME) in tumor progression and survival. Possibly, the BMBC cells are also similarly influenced by the ECM of the metastatic niche; therefore, understanding the effect of the metastatic ECM on BMBC cells is imperative. Herein, we assessed the impact of various ECM components (i.e., Tenascin C, Laminin I, Collagen I, Collagen IV, and Fibronectin) on brain metastatic human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) cell lines in vitro. The highly aggressive TNBC cell line was minimally affected by ECM components exhibiting no remarkable changes in viability and morphology. On the contrary, amongst various ECM components tested, the HER2-positive cell line was significantly affected by Laminin I with higher viability and demonstrated a distinct spread morphology. In addition, HER2-positive BMBC cells exhibited resistance to Lapatinib in presence of Laminin I. Mechanistically, Laminin I-induced resistance to Lapatinib was mediated in part by phosphorylation of Erk 1/2 and elevated levels of Vimentin. Laminin I also significantly enhanced the migratory potential and replicative viability of HER2-positive BMBC cells. In sum, our findings show that presence of Laminin I in the TME of BMBC cells imparts resistance to targeted therapeutic agent Lapatinib, while increasing the possibility of its dispersal and clonogenic survival. [Display omitted] • HER2+ brain metastatic brain cancer cells are responsive to Laminin I. • Laminin I confer resistance to HER2+ BT474Br3 cells against Lapatinib. • Erk 1/2 is involved in Laminin I mediated Lapatinib resistance in BT474Br3 cells. • Laminin I enhances Lapatinib mediated Vimentin expression in BT474Br3 cells. • Migration and clonogenic survival of BT474Br3 cells are augmented by Laminin I. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is the fourth most common cancer among female patients. The primary cause of all types of cervical cancer is human papillomavirus (HPV), which was projected to account for 5,70,000 reported cases in 2018. Two HPV strains (16 and 18) account for 70 % of cervical abnormalities and precancerous cervical cancers. CC is one of the main causes of the 17 % cancer-related death rate among Indian women between the ages of 30 and 69 is CC. The side effects of the currently approved treatments for cervical cancer could endanger the lives of women affected by the illness. Thus, probiotics may be extremely important in the management of CC. Numerous studies on probiotics and their potential for use in cancer diagnosis, prevention, and treatment have been conducted. This review describes the enhancement of the immune system, promotion of a balanced vaginal microbiome, and decreased risk of secondary infections, which have anti-inflammatory effects on the body. Probiotics have the potential to reduce inflammation, thereby adversely affecting cancer cell growth and metastasis. During the course of antibiotic therapy, they support a balanced vaginal microbiome. Oncogenic virus inactivation is possible with probiotic strains. In postmenopausal women, the use of vaginal probiotics helps lessen menopausal symptoms caused by Genitourinary Syndrome of Menopause (GSM). The antitumor effects of other medications can be enhanced by them as potential agents, because they can both promote the growth of beneficial bacteria and reduce the quantity of potentially harmful bacteria. The development of tumors and the proliferation of cancer cells may be indirectly affected by the restoration of the microbial balance. Probiotics may be able to prevent and treat cervical cancer, as they seem to have anticancer properties. To identify probiotics with anticancer qualities that can supplement and possibly even replace traditional cancer treatments, further investigation is required, including carefully planned clinical trials. • HPV, particularly strains 16 and 18, is the primary cause of cervical cancer, contributing to 70 % of precancerous conditions and diagnosed cases. • Cervical cancer ranks as the fourth most common cancer among women globally and causes significant mortality, especially in Indian women aged 30–69. • Probiotics may play a crucial role in managing cervical cancer by enhancing immune responses, promoting a balanced vaginal microbiome, and reducing the risk of secondary infections. • During treatments like antibiotics and radiotherapy, probiotics can support vaginal health and potentially mitigate side effects like Radiation Induced Diarrhea (RID). • Further research is necessary to fully harness probiotics' anticancer properties, which could complement or even replace conventional cancer treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthetic cannabinoids have anti-angiogenic and proapoptotic effects in various cancer types. • 1H-15N HSQC and 1H-15N HMBC were used for the structural elucidation of 14. • Compound 17 markedly increased proapoptotic genes. • Fluorine substitution on the indole increased inhibitory activity. • 17 fits tightly into the active site of the CB2 receptor in silico results. Cannabinoids bind to cannabinoid receptors CB1 and CB2 and their antitumoral activity has been reported against some various cancer cell lines. Some synthetic cannabinoids possessing indole rings such as JWH-015 and JWH-133 particularly bind to the cannabinoid CB2 receptor and it was reported that they inhibit the proliferation and growth of various cancer cells without their psychoactive effects. However, the pharmacological action mechanisms of the cannabinoids are completely unknown. In this study, we report the synthesis of some new cannabinoidic novel indoles and evaluate their anticancer activity on various cancerous and normal cell lines (U87, RPMI 8226, HL60 and L929) using several cellular and molecular assays including MTT assay, real-time q-PCR, scratch assay, DAPI assay, Annexin V-PE/7AAD staining, caspase3/7 activity tests. Our findings indicated that compounds 7 , 10 , 13 , 16 , and 17 could reduce cell viability effectively. Compound 17 markedly increased proapoptotic genes (BAX, BAD, and BIM), tumor suppressor gene (p53) expression levels as well as the BAX/BCL-2 ratio in U87 cells. In addition, 17 inhibited cell migration. Based on these results, 17 was chosen for determining the mechanism of cell death in U87 cells. DAPI and Annexin V-7AAD staining results showed that 17 induced apoptosis, moreover activated caspase 3/7 significantly. Hence, compound 17 , was selected as a lead compound for further pharmacomodulation. To rationalize the observed biological activities of 17 , our study also included a comprehensive analysis using molecular docking and MD simulations. This integrative approach revealed that 17 fits tightly into the active site of the CB2 receptor and is involved in key interactions that may be responsible for its anti-proliferative effects. [ABSTRACT FROM AUTHOR]

The role of kallikrein-related peptidase 5 (KLK5) has been studied in several diseases, including skin and ovarian cancers. However, its role in cervical cancer remains unclear, particularly in regulating the radiation resistance and growth of cervical cancer cells. Radiation resistance of cervical cancer is associated with local recurrence, distant metastasis, and reduced survival. We first analyzed radiotherapy-naive samples and relevant clinical data from patients with cervical cancer who received radiotherapy without surgery or other antitumor treatment from 2014 to 2016. Subsequently, biopsied tissues, in vitro cells, and transplanted tumors in nude mice were investigated. Gene sequencing and clinical data analysis showed that KLK5 overexpression was associated with a poor prognosis post-radiotherapy. In in vitro cell and tumor transplantation experiments, KLK5 overexpression significantly increased radiation resistance. However, downregulating KLK5 expression increased radiosensitivity. Our results confirm that KLK5 is vital to the radioresistance of cervical cancer, and provide a new target and marker for the treatment of radioresistance in cervical cancer. • KLK5 expression is significantly correlated with cervical cancer radioresistance. • KLK5 expression is correlated with negative outcomes, progression, and metastasis. • KLK5 under/overexpression decrease/increase radioresistance in vivo , respectively. • KLK5 may be a promising biomarker for targeted radiotherapy treatment. [ABSTRACT FROM AUTHOR]

In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC. • Solute carrier family 1 member 5 (SLC1A5) is a prognostic factor for poor survival in ccRCC. • SLC1A5 -KO suppressed ccRCC cell proliferation, migration, and invasion in vitro • Inhibition of SLC1A5 had antitumor effects in vitro and in vivo. • SLC1A5 inhibition increased ROS levels and induced cellular senescence. [ABSTRACT FROM AUTHOR]

Sialylation, the final stage of post-translational modification of proteins, is achieved in the Golgi apparatus and is related to the malignant phenotype of cancer. Disialylation of ganglioside (GD3) by St8sia1 and polysialylation by St8sia2 and 4 have been shown to be related to malignant phenotypes; however, di/oligosialylation by St8sia6 is still unknown. In this study, we analyzed the malignant phenotype of St8sia6 and found that upregulation of St8sia6 in melanoma B16 cells increased anchorage-independent cell growth, which was not due to sialic acid cleavage by a sialidase. Moreover, unlike other sialyltransferases, St8sia6 localized to the endoplasmic reticulum (ER). We found that the localization to the Golgi apparatus could be regulated by swapping experiments using St8sia2; however, the malignant phenotype did not change. These data demonstrate that the enhancement of anchorage-independent cell growth by St8sia6 is not due to its localization of ER, but is due to the expression of the protein itself. • The expression of α2,8-sialyltransferase 6, St8sia6, showed a malignant phenotype in B16 mouse melanoma cells. • Unlike other glycosyltransferases and sialyltransferases, St8sia6 localized in the ER. • Abnormal ER-localization of St8sia6 was not responsible for the malignant phenotype of B16 cells. [ABSTRACT FROM AUTHOR]

Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence—TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies. [ABSTRACT FROM AUTHOR]

Histone modification is the key epigenetic mechanism that regulates gene expression. Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that catalyzes dimethylation of histone H3 (H3R17) at arginine 17. Lately, it has been suggested that CARM1 is associated with human carcinogenesis, and the CARM1-selective inhibitor, TP-064, has been shown to be a potential therapeutic agent for multiple myeloma. However, the physiological significance of CARM1 in endometrial cancer remains unclear. Therefore, we aimed to explore the role of CARM1 and the effect of TP-064 in endometrial cancer. To this end, we analyzed CARM1 expression in endometrial cancer using quantitative real-time polymerase chain reaction and examined the antitumor mechanism with CARM1 knockdown endometrial cancer cells. Moreover, we evaluated the therapeutic capability of TP-064 in endometrial cancer cells. CARM1 was remarkably overexpressed in 52 endometrial cancer tissues compared to normal endometrial tissues. The growth of CARM1 knockdown endometrial cancer cells was suppressed and CARM1 knockdown induced apoptosis. TP-064 also inhibited endometrial cancer cell growth and declined the number of endometrial cancer cell colonies. These data suggest that CARM1 may be a powerful therapeutic target for endometrial cancer. • CAMR1 was significantly overexpressed in 52 endometrial cancer tissues. • CARM1 -knockdown suppressed endometrial cancer cell growth and induced apoptosis. • A selective inhibitor of CARM1 TP-064 suppressed endometrial cancer cell growth. [ABSTRACT FROM AUTHOR]

p38δ is a member of p38 mitogen-activated protein kinases (MAPKs) family that displays cell- and tissue-specific expression patterns. Recent studies demonstrate that p38δ is centrally involved in several pathologic events, such as diabetes, neurodegeneration diseases, inflammatory diseases, and cancer, and suggest that it may be a potential target for diagnosis and therapy of specific diseases. A nanobody is a new type of antibody that exhibits high antigen-binding activity, solubility, stability, and easy production. This study utilized phage display to isolate nanobodies specifically against p38δ from a fully synthetic nanobody library. Two of them, nanobodies Nb13-6 and Nb13-1, display high binding activity to p38δ, less cross-reactivity with other p38 MAPKs, and high thermal and pH stabilities. Modeling and docking analysis indicated that Nb13-6 is mostly linked to the activation loop of p38δ. Furthermore, detailed studies revealed that Nb13-6 inhibited the protein kinase activity of p38δ and the growth of cancer cells. Therefore, this study provides p38δ-specific nanobodies that are promisingly exploited for diagnosing and treating p38δ-associated diseases. • The isolated nanobodies specifically bind to p38δ. • Anti-p38δ nanobody Nb13-1 and Nb13-6 display high thermal and pH stability. • Nanobody Nb13-6 binds the activation loop of p38δ. • Nanobody Nb13-6 inhibits the protein kinase activity of p38δ and the growth of breast cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel c-MYC G4 ligand was developed by migrating the benzene group on a carbazole-benzothiazolium scaffold. • The ligand exhibits considerable specificity to the c-MYC G4, which was distinguished from other small-molecule ligands. • The ligand may cause transcriptional inhibition of the c-MYC oncogene instead of other G4-mediated oncogenes. c-MYC is one of the most important oncogenes, which is overexpressed in many cancers, and is highly related to development, metastasis, and drug resistance of cancers. The G4 structure in the promoter of c-MYC oncogene contributes a lot to the gene transcriptional mechanism. Small-molecule ligands binding to the c-MYC G4 appear to be a new class of anticancer agents. However, selective ligands for the c-MYC G4 over other G4s have been rarely reported. In this study, we reported a novel fluorescent ligand by migrating the benzene group on a carbazole-benzothiazolium scaffold, which was demonstrated to exhibit considerable specificity to the c-MYC G4, which was distinguished from other small-molecule ligands. The further cellular experiments suggested that this ligand may indeed target the promoter G4 and cause apparent transcriptional inhibition of the c-MYC oncogene instead of other G4-mediated oncogenes, which thereby resulted in cancer cell growth inhibition. Collectively, this study provided a good example for developing specific c-MYC G4 ligands, which may further develop into an effective anticancer agent that inhibit the c-MYC expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four novel Co(II) complexes of vitaminB3-based Phosphoramides were synthesized. • UV–Vis, FT-IR, Atomic Absorption (AAS), and 31PNMR spectroscopies besides Mass spectrometry, CHN, and Molar conductivity methods were utilized to characterize the synthesized complexes. • In vitro anticancer activity of each complex tested on two cancer cell lines (MCF-7 and MDA-MB-231) and one Normal cell line (MCF-10A). • The complexes exhibited excellent anti-cancer activities and induced MCF-7 and MDA-MB-231cell apoptosis. • All four complexes exhibited very low cytotoxicity on the Normal cell line (MCF-10A), indicating their high safety (much safer than Cisplatin). • Selectivity Index (SI=IC 50 of Normal Cell / IC 50 of Cancer Cell) values of our complexes were 77–93 times higher than those for Cisplatin, and 32–54 times higher than those for the registered breast cancer drug, Doxorubicin. Nicotinamide, known as Vitamin-B3, has shown promising potential in improving various medical conditions. Carbacylamidophosphates (CAPh) are versatile phosphoramide ligands with a wide range of applications in both biochemistry and chemistry. Herein, to obtain compounds with enhanced anticancer activity and study the effect of the structure on this activity, four new Co(II) complexes of vitaminB3-based CAPh ligands with the formula of CoCl 2 [3- NC 5 H 4 CONHPO (NC 5 H 10) 2 ] 2 (C 1), CoCl 2 [3- NC 5 H 4 CONHPO (NC 5 H 9 CH 3) 2 ] 2 (C 2), CoCl 2 [3- NC 5 H 4 CONHPO (NC 6 H 12) 2 ] 2 (C 3), and CoCl 2 [3- NC 5 H 4 CONHPO (NC 4 H 10) 2 ] 2 (C 4) were designed and synthesized. FT-IR, UV–Vis, Atomic Absorption (AAS), 1H, 13C, and 31PNMR, and Mass spectroscopies beside CHN and Molar conductivity methods were utilized to characterize the synthesized compounds. Using MTT-assay and Flow Cytometry, the anticancer effects of these complexes were studied on three distinct cell lines, including one normal cell line (MCF10A) and two cancer cell lines (MDA-MB-231, MCF-7). Results showed that our ligands could form complexes by coordinating with cobalt, which, not only have a very strong killing effect on cancer cells but also have a higher level of safety for normal cells and are more cost-efficient than Cisplatin. C 3 was the most effective complex at inhibiting the growth of MCF-7 and MDA-MB-231 cells which exhibited a remarkable 97.5 % reduction in cancer cell growth and a Selectivity Index up to > 37. This is an impressive 93 and 54 times more selective and safer than commonly used drugs like Cisplatin and Doxorubicin, respectively. Flow Cytometry analysis shows complex-induced breast cancer cell apoptosis. The ligands' amine structure and ring size can directly impact the complexes' anticancer effect and safety for normal cells. [ABSTRACT FROM AUTHOR]

• Summarize the changes in hormone levels before and after pregnancy. • Review the roles of hormones in mammary gland development and breast cancer progression. • Illuminate the role of pregnancy and lactation on breast cancer risk. • Discuss theories and potential mechanisms behind pregnancy's dual effect on breast cancer risk. Reproductive history is one of the strongest risk factors for breast cancer in women. Pregnancy can promote short-term breast cancer risk, but also reduce a woman's lifetime risk of breast cancer. Changes in hormone levels before and after pregnancy are one of the key factors in breast cancer risk. This article summarizes the changes in hormone levels before and after pregnancy, and the roles of hormones in mammary gland development and breast cancer progression. Other factors, such as changes in breast morphology and mammary gland differentiation, changes in the proportion of mammary stem cells (MaSCs), changes in the immune and inflammatory environment, and changes in lactation before and after pregnancy, also play key roles in the occurrence and development of breast cancer. This review discusses the dual effects and the potential mechanisms of pregnancy on breast cancer risk from the above aspects, which is helpful to understand the complexity of female breast cancer occurrence. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cancer TME proliferate, induce angiogenesis and sometimes metastasize. • Mitochondria as an organelle is an adjuvant to nucleus in cancer pathogenesis. • The changes in the gene are strongly related to cellular metabolism and metabolic reprogramming. Reprogramming the TME will have a direct effect on the immune cells' metabolism. • Cancer energy reprogramming mechanisms and enzyme degradation pathways defines the cancer pathogenicity. • This activity series involved with reduced lactate production, the specific immune cell responses due to the energy reprogramming. Cancer as an uncontrolled growth of cells due to existing mutation in host cells that may proliferate, induce angiogenesis and sometimes metastasize due to the favorable tumor microenvironment (TME). Since it kills more than any disease, biomedical science does not relent in studying the exact pathogenesis. It was believed to be a problem that lies in the nucleus of the host cells; however, recent oncology findings are shifting attention to the mitochondria as an adjuvant to cancer pathogenesis. The changes in the gene are strongly related to cellular metabolism and metabolic reprogramming. It is now understood that reprogramming the TME will have a direct effect on the immune cells' metabolism. Although there are a number of studies on immune cells' response towards tumor energy reprogramming and cancer progression, there is still no existence with the updated collation of these immune cells' response to distinct energy reprogramming in cancer studies. To this end, this mini review shed some light on cancer energy reprogramming mechanisms and enzyme degradation pathways, the cancer pathogenicity activity series involved with reduced lactate production, the specific immune cell responses due to the energy reprogramming. This study highlighted some prospects and future experiments in harnessing the host immune response towards the altered energy metabolism due to cancer. [ABSTRACT FROM AUTHOR]

• Extensive loss HLA-class-I expression occurs 76.6% of breast carcinomas. • HLA-preservation is associated with high TIL-density and low HIF1α expression. • Hypoxia suppresses HLA-class-I expression in breast cancer cell lines. • Induction of HLA following incubation with IFNγ is abrogated under hypoxia. • HLA-preservation is linked with better distant metastasis-free survival. Loss of HLA-class-I molecule expression by cancer cells is a frequent event in human tumors that may lead to immune evasion from cytotoxic T -cells. We examined the expression patterns of HLA-class-I molecules in a series of 175 patients with operable breast cancer (BCa). Extensive loss of BCa cell HLA-class-I expression was noted 76.6 % of patients (27.5 % complete loss). A significant association of HLA-preservation with high TIL-density (p = 0.001) was documented. Preservation of HLA was evident only in BCa carcinomas with low HIF1α expression and high TIL-density. Cell line experiments (MCF7 and T47D) showed that induction of HLAs in cancer cells following incubation with lymphocytes or IFNγ, was abrogated under hypoxic conditions. HLA-preservation was linked with better distant metastasis-free survival (p = 0.01), which was confirmed also in multivariate analysis (p = 0.02, HR 3.17). Studying the expression of HLA-class-I molecules in parallel with TIL-density and HIF1α expression may identify subgroups of BCa patients who would benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Haspin is considered a promising target for cancer therapy owing to its overexpression in the most prevalent cancers. • A novel class of indazole derivatives as potent and selective haspin inhibitors was developed. • Compound 21 exhibited marked potency (IC 50 = 77.7 nM) and selectivity for haspin over common off-targets. • Compounds 5 and 21 inhibited the growth of many NCI cancerous cell lines. • The 5-(4-Pyridinyl)indazole scaffold serves as a lead for the development of novel anticancer agents. Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N 1 of the indazole ring with m -hydroxyphenyl acetic acid yielded compound 21 with an IC 50 value of 78 nM against haspin. This compound showed a meaningful selectivity over 15 of the most common off-targets, including Clk 1–3 and Dyrk1A, 1B, and 2. The most potent haspin inhibitors 5 and 21 effectively inhibited the growth of the NCI-60 cancer cell lines, further emphasizing the success of our scaffold as a new selective lead for the development of anti-cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

Discovery and SAR Analysis of N and S Substituted Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth with High Selectivity via c-Src Kinase Inhibition, Apoptotic effect, and DNA Fragmentation. [Display omitted] • Pyrazolopyrimidine scaffold with prominenet anticancer activity. • The cytotoxic activity was tested against targeted cancer cell lines. • The in-vitro inhibitory effect of active analogs against c-Src kinase was promising and selective. • Compounds 7c with N -propyl side chain was able to induce cell cycle arrest at G2/M phase causing apoptosis. In this work, readily achievable synthetic pathways were utilized for construction of a library of N /S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC 50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N -substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N -propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N -substitution as promising candidates for the treatment of TNBC type of breast cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • This paper has showed four new drimane-type sesquiterpenoids and two new nucleosides from the Helicoma septoconstrictum. • Helicoside C (compounds 4) mediated intracellular ROS and mitochondrial dependent apoptosis in ovarian cancer A2780 cells. • Helicoside C could suppress the STAT3′s phosphorylation in A2780 cells. Four new drimane-type sesquiterpenoids and two new nucleoside derivatives (1–6), were isolated from the fungus Helicoma septoconstrictum. Their structures were determined based on the combination of the analysis of their HR-ESI-MS, NMR, ECD calculations data and acid hydrolysis. All the isolated compounds were detected for their bio-activities against MDA-MB-231, A549/DDP, A2780 and HepG2 cell lines. Helicoside C (4) exhibited superior cytotoxicity against the A2780 cell line with IC 50 7.5 ± 1.5 µM. The analysis of reactive oxygen species (ROS) revealed that Helicoside C induced an increase in intracellular ROS. Furthermore, the flow cytometry and mitochondrial membrane potential (MMP) analyses unveiled that Helicoside C mediated mitochondrial-dependent apoptosis in A2780 cells. The western blotting test showed that Helicoside C could suppress the STAT3′s phosphorylation. These findings offered crucial support for development of H. septoconstrictum and highlighted the potential application of drimane-type sesquiterpenoids in pharmaceuticals. [ABSTRACT FROM AUTHOR]

[Display omitted] • USP2a, a member of the ubiquitin-specific protease (USP) family, is a promising target for cancer therapy. • This study optimized the structure of ML364, leading to the identification of compound 8v as a potent USP2a inhibitor. • Compound 8v selectively reduced USP2a substrate levels and inhibited cancer cell growth. Ubiquitination is a representative post-translational modification that tags target proteins with ubiquitin to induce protein degradation or modify their functions. Deubiquitinating enzymes (DUBs) play a crucial role in reversing this process by removing ubiquitin from target proteins. Among them, USP2a has emerged as a promising target for cancer therapy due to its oncogenic properties in various cancer types, but its inhibitors have been limited. In this study, our aim was to optimize the structure of ML364, a USP2a inhibitor, and synthesize a series of its derivatives to develop potent USP2a inhibitors. Compound 8v emerged as a potential USP2a inhibitor with lower cytotoxicity compared to ML364. Cellular assays demonstrated that compound 8v effectively reduced the levels of USP2a substrates and attenuated cancer cell growth. We confirmed its direct interaction with the catalytic domain of USP2a and its selective inhibitory activity against USP2a over other USP subfamily proteins (USP7, 8, or 15). In conclusion, compound 8v has been identified as a potent USP2a inhibitor with substantial potential for cancer therapy. [ABSTRACT FROM AUTHOR]

Early-stage gastric cancer (GC) is asymptomatic. How to diagnose the early-stage GC is challenging. The sensitivity and specificity of diagnosing signatures for early-stage patients are still poor. Elastic-net-based analysis was used to identify potential diagnostic signatures of early-stage GC. The expression level of candidate gene was evaluated by immunohistochemistry staining. The potential function of candidate gene was verified by overexpressing in vitro. Consensus genes (including GAMT) were identified using the different strengths of the penalty. Surprisingly, GAMT was still identified even if some multicollinear variables were deleted directly. IHC staining showed that there are no GAMT-positive signals in the cell nuclei of all tumor tissues, while GAMT does express in nuclei of adjacent normal tissue. There are 16.33% positive cell nuclei in paracancerous tissues. In addition, the number of larger-area colonies of overexpression-GAMT group, empty-vector group, and AGS group is 70 ± 29.21 , 151.33 ± 15.95 , and 111.67 ± 22.03 , respectively. Number of larger colonies in group with overexpression of GAMT is significantly less than control groups. Elastic-net-penalty-based workflow is a effective tool to identify diagnostic biomarker for early-stage solid tumor. GAMT has strong potential to be the diagnostic biomarker for the early-stage GC. • GAMT can be used as potential diagnostic marker for early-stage gastric cancer. • Overexpressing GAMT could suppress the growth of gastric cancer cell. • Elastic-net-penalty-based workflow is effective to identify diagnostic marker. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) is a non-coding RNA molecule that lacks polyadenylated tails and is highly stable, abundant, and conserved in human cells. CircRNAs can serve as a competing endogenous RNA (ceRNA) to sponge microRNAs (miRNA) and block their effects on target mRNA expression. CircRNAs also have possible relevance to cancer and therefore may be considered as ideal biomarkers for monitoring cancer progression. Of the about 300,000 predicted human circRNAs, only a few have validated biological functions related to cancer. To better understand the ceRNA role of circRNAs in colorectal cancer (CRC), we performed genome-wide circRNA-based RNA-sequencing (RNA-Seq) on nine CRC tumor samples and their paired histologically normal adjacent tissue samples. By profiling the mRNA expression in the same patients, we further explored the expression correlation between circRNAs and mRNAs generated from the same parental gene. Focusing on the concordant differential expression between circRNAs and mRNAs, we substantially reduced the regulatory noise. In total, we identified 694 circRNA-mRNA pairs that were consistently up or downregulated between tumor and normal tissues. These 694 circRNA-mRNA pairs are from 182 protein-coding genes associated with hormone responses and chemotaxis. Of these 182 genes, 43 are downstream targets of three highly conserved miRNAs (miR-410-3p, miR-135a, and miR-30a). Interestingly, these 43 genes are highly mutated in another cohort from eight independent CRC studies, which have significant effects on patient survival time. Focusing on miR-410-3p and its target oncogene MET , we experimentally validated the ceRNA regulatory motif of circMET. Notably, circMET is substantially upregulated in CRC cell lines and could promote cell proliferation and growth. By confirming the regulatory relationship between miR-410-3p and circMET, we propose a new mechanism for the observed sustained activation of MET in CRC. In conclusion, our work identifies a novel regulatory role of circMET and provides a potential diagnostic biomarker for CRC. • Genome-wide circRNA and mRNA profiling from the same colorectal cancer patient is presented. • A generalized computational and experimental framework to explore the circRNA-based gene regulation is proposed. • Convergence of circRNA and mRNA from the same host gene is used to build competing endogenous network. • Identification of circMET-miR-410-3p-MET regulatory motif is highlighted. • The regulatory relationships among circMET-miR-410-3p-MET is confirmed in colorectal cell lines. [ABSTRACT FROM AUTHOR]

Metastatic spread in breast cancer patients is the major driver of cancer-related deaths. A unique subset of cells disseminated from pre-invasive or primary tumor lesions are recognized as the main seeds for metastatic outgrowth. Disseminated cancer cells (DCCs) can migrate to distant organs and settle in a dormant state for a prolonged period until they emerge to overt metastases. Understanding the biology of breast cancer cells dissemination, dormancy and reactivation to form overt metastases has become an important focus. In this review, we discuss the recent advancements of molecular pathways involving breast cancer cell dissemination, role of chemokine-chemokine receptor networks in DCCs migration, DCCs phenotypic heterogeneity and unique genes signatures in tumor dormancy, microenvironmental regulation and specific niches that favors DCCs homing and dormancy. In addition, we also discuss recent findings relating to the role of immune response on DCC dissemination and dormancy. With recent advances in the field of immunotherapy/targeted therapy and its beneficial effects in cancer treatment, this review will focus on their impact on DCCs, reversal of stemness, tumor dormancy and metastatic relapse. [ABSTRACT FROM AUTHOR]

Abnormal activation of the mechanistic target of rapamycin (mTOR) signaling is commonly observed in many cancers and attracts extensive attention as an oncology drug discovery target, which is encouraged by the success of rapamycin and its analogs (rapalogs) in treatment of mTORC1-hyperactive cancers in both pre-clinic models and clinical trials. However, rapamycin and existing rapalogs have typically short-lasting partial responses due to drug resistance, thereby triggering our interest to investigate a potential mTORC1 inhibitor that is mechanistically different from rapamycin. Here, we report that hayatine, a derivative from Cissampelos , can serve as a potential mTORC1 inhibitor selected from a natural compound library. The unique properties owned by hayatine such as downregulation of mTORC1 activities, induction of mTORC1's translocation to lysosomes followed by autophagy, and suppression on cancer cell growth, strongly emphasize its role as a potential mTORC1 inhibitor. Mechanistically, we found that hayatine disrupts the interaction between mTORC1 complex and its lysosomal adaptor RagA/C by binding to the hydrophobic loop of RagC, leading to mTORC1 inhibition that holds great promise to overcome rapamycin resistance. Taken together, our data shed light on an innovative strategy using structural interruption-based mTORC1 inhibitors for cancer treatment. • Identification of compounds against cancer cells with mTORC1 inhibition using cell size alteration as the indicator. • Hayatine inhibited mTORC1 and induced autophagic influx. • Hayatine blocked amino acid-induced mTORC1 activation. • Hayatine working as mTOR-RagA/C interaction disruptor under amino acid treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future. • Cox15 was highly expressed in lung cancer and serves as new prognostic biomarker. • Nrf2 specifically binds to Cox15 promoter and triggers Cox15 expression in transcriptional level. • Aripiprazole executives a profoundly suppressive effects on lung cancers cells growth through inhibiting Cox15 expression. [ABSTRACT FROM AUTHOR]

Prostate cancer, the most common non-cutaneous male cancer, is a public health problem with a third prevalence worldwide. PYCR1 and miR-1207-5p dysregulations were found in cancer progression. Our study aims to reveal the biological role of miR-1207-5p-PYCR1 axis in prostate cancer progression. First, we investigated the expression of miR-1207-5p in prostate cancer tissues and cell lines by RT-qPCR. Next, we confirmed miR-1207-5p targeting PYCR1 by luciferase assay. CCK-8 assay, BrdU assay, flow cytometry, and tanswell assay were applied for examining cell proliferation, apoptosis, and invasion in prostate cancer cells, respectively. In the present study, decreased miR-1207-5p expression was obviously observed in prostate cancer tissues and cells. Upregulation of miR-1207-5p hampered cellular proliferation and invasion, while enhanced cellular apoptosis. In addition, upregulation of PYCR1 elevated cell proliferation and invasion, but repressed apoptosis of prostate cancer cells. Moreover, miR-1207-5p inhibited the expression of PYCR1 to repress prostate cancer tumorigenesis. MiR-1207-5p inhibited the expression of PYCR1 to repress the progression of prostate cancer by inhibiting cell growth and elevating cell apoptosis. Overall, our study clarifies the biological role of miR-1207-5p-PYCR1 axis in prostate cancer progression, which might be effective biomarkers for clinical treatment of prostate cancer. • miR-638 and PYCR1 were the key regulators in prostate cancer. • MiR-1207-5p repressed cell proliferation and migration and promoted cell apoptosis in prostate cancer. • MiR-1207-5p directly targeted PYCR1. • MiR-1207-5p targeting PYCR1 suppressed the progression of prostate cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Lanthanide-doped upconversion nanoparticles (UCNPs) have been extensively investigated due to their unique capabilities of upconverting near-infrared light (NIR) to visible/ultraviolet emission. However, use of conventional Yb-based UCNPs under 980 nm excitation for biomedical applications is limited due to the overheating caused by the strong light absorption by water at this wavelength. Although this could be improved by using Nd3+-Yb3+ codoped UCNPs and changing the excitation wavelength to 808 nm, the amount of Nd3+ doping is usually below 20 mol% due to the lattice strain in highly Nd-doped core–shell structures. In this study, we report Nd3+-sensitized NaYF 4 :Yb,Er@NaLuF 4 :Nd@NaLuF 4 UCNPs, in which the NaLuF 4 in the intermediate shell can accommodate more structural changes caused by the Nd3+ doping, and allow for high concentration of Nd3+ doping (up to 50 mol%). Due to such high Nd3+ doping in the nanostructure, the red and green upconversion emissions of as-synthesized UCNPs are significantly increased upon 808 nm excitation, which are used to activate two photosensitizer drugs, MC540 (merocyanine 540) and FePc (iron phthalocyanine), for the dual photodynamic and photothermal therapy. The results show that the generation of reactive oxygen species (ROS) upon 808 nm light excitation is substantially boosted due to the synergistic therapeutic effect, which significantly prohibits the growth of cancer cells. It is believed that the nanoplatform specially developed in this study can solve the overheating issue associated with the 980 nm light excitation and the combined photodynamic and photothermal therapy can significantly improve the cancer therapy efficacy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma – a process that can take up to 15–20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs — microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) — and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection is a crucial factor in the development of gastric cancer (GC). Molecular therapeutic targets and mechanisms contributing to H. pylori infection-associated GC induction are poorly understood and this study aimed to fill that research gap. We found that the nuclear receptor estrogen-related receptor gamma (ESRRG) is a candidate factor influencing H. pylori infection-driven GC. ESRRG suppressed H. pylori infection and cell growth induced by H. pylori infection in GC cells and organoid models In addition, H. pylori infection downregulates ESRRG expression. Gene expression profiling revealed that trefoil factor 1 (TFF1), a well-known tumor suppressor in GC, is a downstream target of ESRRG. Mechanistically, ESRRG directly binds to the TFF1 promoter and induces TFF1 gene expression. Furthermore, TFF1 activation by ESRRG was inhibited by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p65, which is induced by inflammation, such as by H. pylori infection. Our current study provides new molecular insights into how ESRRG regulates H. pylori infection, contributing to GC development. We suggest that modulation of ESRRG-suppressing H. pylori infection could be a therapeutic target for the treatment of GC patients. • Nuclear receptor, ESRRG has a crucial role in Helicobacter pylori infection-leading gastric cancer. • ESRRG-TFF1 axis modulates Helicobacter pylori infection and suppresses cancer cell growth. • ESRRG activity is pivotal for gastric cancer promotion. [ABSTRACT FROM AUTHOR]

Comprised of a complex network of numerous intertwining pathways, the Ca2+ signalling nexus is an essential mediator of many normal cellular activities. Like many other such functions, the normal physiological activity of Ca2+ signalling is frequently co-opted and reshaped in cases of breast cancer, creating a potent oncogenic drive within the affected cell population. Such modifications can occur within pathways mediating either Ca2+ import (e.g. TRP channels, ORAI-STIM1) or Ca2+ export (e.g. PMCA), indicating that both increases and decreases within cellular Ca2+ levels have the potential to increase the malignant potential of a cell. Increased understanding of these pathways may offer clinical benefit in terms of both prognosis and treatment; patient survival has been linked to expression levels of certain Ca2+ transport proteins, whilst selective targeting of these factors with novel anti-cancer agents has demonstrated a variety of anti-tumour effects in in vitro studies. In addition, the activity of several Ca2+ signalling pathways has been shown to influence chemotherapy response, suggesting that a synergistic approach coupling traditional chemotherapy with Ca2+ targeting agents may also improve patient outcome. As such, targeted modulation of these pathways represents a novel approach in precision medicine and breast cancer therapy. [ABSTRACT FROM AUTHOR]

In this review we highlighted the newest aspects concerning the physiopathology of breast cancer metastatization into the bone including: a) in situ biomarkers of breast cancer metastatic diseases, b) biological processes related to the origin of metastatic cells (epithelial to mesenchymal transition), c) the nature and the possible role of Breast Osteoblast-Like Cells in the formation of bone lesions and d) the prognostic value of breast microcalcifications for the bone metastatic disease. In addition, the more recent data about the biology of breast cancer metastatic process and the origin and function of Breast Osteoblast-Like Cells have been analyzed to propose the use of molecular imaging investigations able to identify early neoplastic lesions with high propensity to form bone metastasis in vivo. [ABSTRACT FROM AUTHOR]

Herein we report the construction of a series of MSNs with adjustable specific surface area, size, and pore structure, depending on the different silicon monomers selected. The optimized MSN showed large specific surface area and appropriate size distribution for efficiently anchoring doxorubicin (DOX) through the imine linkage formed. Based on the remarkable features of the unique MSN, a novel MSN-based drug delivery system was prepared through the introduction of polydopamine/manganese oxide (PDA/MnO 2) coating, which reduced the premature leakage of drugs in physiological environments, and yet facilitated drug release when destroyed by responding to endogenous glutathione (GSH) at the tumor sites. Notably, the transformation of MnO 2 to Mn2+ resulted in the collapse of the PDA/MnO 2 coating, which facilitated drug release and therefore indicated the controlled release feature. It was demonstrated that the drug-loaded MSN-based drug delivery system delivered drugs into cancer cells and showed effective inhibition against cancer cell growth. [Display omitted] Rapid progress has been made for mesoporous silica nanoparticle (MSN) in recent years; however, efforts to fabricate MSN with adjustable size have been met with limited advancement in drug delivery, especially for the synthesis of MSN with adjustable size in the range of 150–300 nm. Herein we report the construction of a series of MSNs with adjustable specific surface area, size, and pore structure, depending on the different silicon monomers selected. The optimized MSN showed large specific surface area and appropriate size distribution for efficiently anchoring doxorubicin (DOX) through the imine linkage formed. Based on the remarkable features of the unique MSN, a novel MSN-based drug delivery system was prepared through the introduction of polydopamine/manganese oxide (PDA/MnO 2) coating, which reduced the premature leakage of drugs in physiological environments, and yet facilitated drug release when destroyed by responding to endogenous glutathione (GSH) at the tumor sites. Notably, the transformation of MnO 2 to Mn2+ resulted in the collapse of the PDA/MnO 2 coating, which facilitated drug release and therefore indicated the controlled release feature. It was demonstrated that the drug-loaded MSN-based drug delivery system delivered drugs into cancer cells and showed effective inhibition against cancer cell growth. These results suggested that the emergence of MSN with adjustable size can expand the application of MSN in drug delivery. [ABSTRACT FROM AUTHOR]

Liver metastases from gastrointestinal and non-gastrointestinal malignancies remain a major cause of cancer-related mortality and a major clinical challenge. The liver has unique properties that facilitate metastatic expansion, including a complex immune system that evolved to dampen immunity to neoantigens entering the liver from the gut, through the portal circulation. In this review, we describe the unique microenvironment encountered by cancer cells in the liver, focusing on elements of the innate and adaptive immune response that can act as a double-edge sword, contributing to the elimination of cancer cells on the one hand and promoting their survival and growth, on the other. We discuss this microenvironment in a clinical context, particularly for colorectal carcinoma, and highlight how a better understanding of the role of the microenvironment has spurred an intense effort to develop novel and innovative strategies for targeting liver metastatic disease, some of which are currently being tested in the clinic. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor extracellular domain III (EGFR-ECDIII) protein is a promising target of anti-cancer research, and its production in Escherichia coli would thus represent significant benefits. However, despite its moderate size (19 kDa), the expression of EGFR-ECDIII in E.coli is hampered by the presence of multiple cysteines producing misfolded proteins with incorrect S-S bonds. In our study, we show that a short 12-residue solubility enhancing peptide (SEP) tag containing nine arginines (C9R) attached at the C-terminus of EGFR-ECDIII reduces the inclusion body formation and increases the final yield by six times (20 mg/L). EGFR-ECDIII-C9R purified from the soluble fraction eluted as a sharp single RP-HPLC peak, suggesting a single S-S bond pairing. Biophysical characterization using circular dichroism, fluorescence, and light scattering confirmed its native-like properties together with reversible thermal denaturation. The binding activity of EGFR-ECDIII-C9R to anti-EGFR-VHH7D12, a single-domain antibody with specific binding to the ECDIII, was assessed by sandwich ELISA. Further, we produced anti-EGFR-ECDIII-C9R antisera in mouse models and anti-sera inhibited A431 cancer cells' growth. These results demonstrate that the SEP tag enables the rapid production of the multiple disulfide-bonded EGFR-ECDIII in E. coli having native-like biophysical properties and producing neutralizing antibodies. • C9R tag increased the solubility of a multi-SS-bonded EGFR-ECDIII-C9R in E.coli and yield by 6 fold. • CD, fluorescence, and light scattering confirmed EGFR-ECDIII-C9R's native-like properties. • Binding of EGFR-ECDIII to VHH7D12, a single-domain antibody, was demonstrated by sandwich ELISA. • EGFR-ECDIII-C9R produced high titer anti-(native) EGFR antisera inhibiting cancerous cell growth. [ABSTRACT FROM AUTHOR]

PUMA (p53-upregulated modulator of apoptosis) is localized in mitochondria and a direct target in p53-mediated apoptosis. p53 elicits mitochondrial apoptosis via transcription-dependent and independent mechanisms. p53 is known to induce apoptosis via the transcriptional induction of PUMA, which encodes proapoptotic BH3-only members of the Bcl-2 protein family. However, the transcription-independent mechanisms of human PUMA remain poorly defined. For example, it is not known whether PUMA interacts directly with the DNA binding domain (DBD: residues 92–293) of p53 in vitro. Here, the structure of the complex between the DBD of p53 and PUMA peptide was elucidated by X-ray crystallography. Isothermal titration calorimetry showed that PUMA peptide binds strongly with p53 DBD, and the crystal structure of p53-PUMA peptide complex revealed it contains four molecules of p53 DBD and one PUMA peptide per asymmetric unit in space group P 1. PUMA peptide bound to the N-terminal residues of p53 DBD. A cell proliferation assay demonstrated PUMA peptide inhibited the growth of a lung cancer cell line. These results contribute to understanding of the mechanism responsible for p53-mediated apoptosis. • The PUMA gene is a transcriptional target of p53. • The first crystal structure of p53 DBD and PUMA complex was determined. • PUMA peptide inhibited the growth of a lung cancer cell line. • These findings provide further insight of potential drug targets for cancer therapy. • The p53 DBD was physically bound to PUMA peptide with an apparent K D value. [ABSTRACT FROM AUTHOR]

In the tumor environment, hypoxia promotes tumor progression, such as cancer cell growth, migration and chemoresistance. This study aimed to evaluate the roles of free fatty acid receptors (FFARs) in the regulation of cancer cell functions under hypoxic conditions, using fibrosarcoma HT1080 cells. HT1080 cells expressed FFAR1 , FFAR2 and FFAR3 genes, but not FFAR4 gene. FFAR1 , FFAR2 and FFAR3 expression levels in HT1080 cells cultured at 1 % O 2 were elevated, compared with 21 % O 2. The cell growth activities of HT1080 cells cultured at 21 % O 2 were inhibited by acetic acid (AA) and propanoic acid (PA), but not 1 % O 2. HT1080 cell motility was markedly reduced by culturing at 1 % O 2. The cell growth and motility of HT1080 cells were enhanced by FFAR2 knockdown. The cell viability to cisplatin (CDDP) of HT1080 cells cultured at 1 % O 2 was increased, compared with 21 % O 2. FFAR2 knockdown suppressed the cell viability to CDDP of HT1080 cells. On the other hand, the cell motility and viability to CDDP of HT1080 cells cultured at 21 % O 2 were suppressed by TUG-770. When HT1080 cells were cultured at 1 % O 2 , the cell motility and viability to CDDP were decreased, correlating with FFAR1 expression level. Moreover, FFAR1 knockdown increased the cell viability to CDDP of HT1080 cells cultured at 1 % O 2. These results suggest that FFAR-mediated signaling plays an important role in the modulation of cellular functions of HT1080 cells under hypoxic conditions. • FFAR1 , FFAR2 and FFAR3 expressions in HT1080 cells were elevated by culturing at 1 % O 2. • FFAR2 inhibited and FFAR3 stimulated cell growth and migration of HT1080 cells cultured at 1 % O 2. • Cell viability to CDDP was enhanced by Gi protein via FFAR2 and FFAR3 in HT1080 cells cultured at 1 % O 2. • HT1080 cell motility and viability to CDDP at 1 % O 2 were suppressed by FFAR1. • FFARs are involved in the modulation of cellular functions of HT1080 cells under hypoxic conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] Pin1 (proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1), as a member of PPIase family, catalyzes cis–trans isomerization of pThr/Ser-Pro amide bonds of its substrate proteins, further regulating cell proliferation, division, apoptosis, and transformation. Pin1 is overexpressed in various cancers and is positively correlated with tumor initiation and progression. Pin1 inhibition can effectively reduce tumor growth and cancer stem cell expansion, block metastatic spread, and restore chemosensitivity, suggesting that targeting Pin1 may be an effective strategy for cancer treatment. Considering the promising therapeutic effects of Pin1 inhibitors on cancers, we herein are intended to comprehensively summarize the reported Pin1 inhibitors, mainly highlighting their structures, biological functions and binding modes, in hope of providing a reference for the future drug discovery. [ABSTRACT FROM AUTHOR]