scholarly journals Integrative Analysis of MALT1 as a Potential Therapeutic Target for Prostate Cancer and its Immunological Role in Pan-Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Haotian Tan ◽  
Yaqi Xie ◽  
Xuebao Zhang ◽  
Shuang Wu ◽  
Hongwei Zhao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathways ◽  
Gene Mutation ◽  
Nude Mice ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Go Analysis

Background: Mucosa-associated lymphoma antigen 1 (MALT1) is an oncogene in subsets of diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue type (MALT) lymphoma. However, the role of MALT1 across cancers, especially in prostate cancer is still poorly understood.Methods: Here, we used several public datasets to evaluate MALT1 expression. Then, PCa cell lines and nude mice were used to investigate the cellular functions in vitro and in vivo. Microarray data were downloaded from The Cancer Genome Atlas and MALT1 was subjected to gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis to identify the biological functions and relevant pathways. Additionally, the correlations between MALT1 expression and mismatch repair (MMR) gene mutation, immune checkpoint gene expression, tumor mutational burden (TMB), and microsatellite instability (MSI) were investigated by Pearson correlation analysis. Moreover, the correlation between MALT1 expression and tumor immune infiltration was analyzed by the Tumor Immune Evaluation Resource (TIMER) database.Results: MALT1 overexpression was significantly correlated with MMR gene mutation levels and crucially promoted proliferation and colony genesis while reducing PCa cell apoptosis levels in vivo and in vitro. MALT1 expression showed strong correlations with immune checkpoint genes, TMB, and MSI in most cancers. The GO analysis indicated that MALT1-coexpressed genes were involved in heterotypic cell-cell adhesion, actin filament-based movement regulation, and action potential regulation. GSEA revealed that MALT1 expression was associated with several signaling pathways, including the NF-κB signaling, Wnt/β-catenin and TGF-β signaling pathways, in PCa. Additionally, MALT1 expression was significantly correlated with the infiltration of immune cells, including B cells, CD8+ T cells, dendritic cells and macrophages, and negatively correlated with CD4+ cell infiltration in PCa.Conclusion: MALT1 expression is higher in pancancer samples than in normal tissues. MALT1 promoted proliferation and colony genesis while reducing PCa cell apoptosis levels, and MALT1 suppression could inhibit xenograft tumor establishment in nude mice. Furthermore, MALT1 expression is closely related to the occurrence and development of multiple tumors in multiple ways. Therefore, MALT1 may be an emerging therapeutic target for a variety of cancers especially PCa.

TRIAP1 Inhibition Activates the Cytochrome c/Apaf-1/Caspase-9 Signaling Pathway to Enhance Human Ovarian Cancer Sensitivity to Cisplatin

Chemotherapy ◽  
2019 ◽  
Vol 64 (3) ◽  
pp. 119-128 ◽  
Author(s):  
Tian-Mei Zhang
Keyword(s):  
Ovarian Cancer ◽  
Nude Mice ◽  
Cell Apoptosis ◽  
Caspase 9 ◽  
Ovarian Carcinoma Cell Line ◽  
Skov3 Cells ◽  
Cyt C ◽  
Sirna Group

Objective: To investigate whether TRIAP1inhibition affects the ovarian cancer cell resistance to cisplatin (DDP) via the Cyt c/Apaf-1/caspase-9 pathway by in vitro and in vivo experiments. Methods: CCK8 assay was performed to find out how treatment with both TRIAP1 siRNA and DDP affects the cell viability of SKOV3 cells and DDP-resistant human ovarian carcinoma cell line SKOV3/DDP. SKOV3/DDP cells were transfected with control siRNA or TRIAP1 siRNA before 24 h of treatment with DDP (5 μg/mL). Flow cytometry was employed to detect cell apoptosis and Western blot to examine the expressions of Cyt c/Apaf-1/caspase-9 pathway-related proteins. SKOV3/DDP cells transfected with control siRNA or TRIAP1 siRNA were subcutaneously injected into BALB/c-nu/nu nude mice followed by the intraperitoneal injection of DDP (4 mg/kg). Cyt c/Apaf-1/caspase-9 pathway in transplanted tumors was detected by immunohistochemistry. Results: TRIAP1 expression declined in SKOV3 cells when compared with SKOV3/DDP cells. The proliferation rate was lower in SKOV3/DDP cells transfected with TRIAP1 siRNA combined with treatment of DDP (1, 2, 4, 6, 8, 16, 32 μg/mL) than in those transfected with control siRNA. Moreover, the TRIAP1 siRNA group had an increased SKOV3/DDP cell apoptosis rate with the activation of the Cyt c/Apaf-1/caspase-9 pathway. During DDP treatment, nude mice in TRIAP1 siRNA group had slower growth and smaller size of transplanted tumor than those in control siRNA group, with increased expression of Cyt c, Apaf-1, and caspase-9. Conclusion: TRIAP1 inhibition may enhance the sensitivity of SKOV3/DDP cells to cisplatin via activation of the Cyt c/Apaf-1/caspase-9 pathway.

scholarly journals Clinical Utility of Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Diagnostic Tool and Potential Therapeutic Target in Prostate Cancer

2019 ◽  
Vol 8 (12) ◽  
pp. 2056 ◽  
Author(s):  
Juan M. Jiménez-Vacas ◽  
Enrique Gómez-Gómez ◽  
Antonio J. Montero-Hidalgo ◽  
Vicente Herrero-Aguayo ◽  
Fernando L-López ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Therapeutic Target ◽  
Xenograft Model ◽  
Grey Zone ◽  
Pathophysiological Role ◽  
Expression Activity ◽  
Du145 Cells

Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g., CDK2/CDK6/CDKN2A expression) aggressiveness parameters. Indeed, GOAT overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa.

scholarly journals Inhibition of LOXL2 Enhances the Radiosensitivity of Castration-Resistant Prostate Cancer Cells Associated with the Reversal of the EMT Process

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Peng Xie ◽  
Hongliang Yu ◽  
Feijiang Wang ◽  
Feng Yan ◽  
Xia He
Keyword(s):  
Prostate Cancer ◽  
Cell Apoptosis ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Du145 Cells ◽  
Androgen Independent

Introduction. Radiotherapy is the mainstay in the treatment of prostate cancer. However, significant radioresistance of castration-resistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. By using bioinformatic data mining methods, LOXL2 was found to be upregulated in both androgen-independent prostate cancer cell lines and radioresistant tumor samples collected from patients with prostate cancer. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. Methods. The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. In studies on the mechanism, we focused on the EMT phenotype changes and cell apoptosis changes induced by LOXL2 knockdown in DU145 cells. The protein levels of three EMT biomarkers, namely, E-cadherin, vimentin, and N-cadherin, were measured by western blotting and immunohistochemical staining. Cell apoptosis after irradiation was measured by flow cytometry and caspase-3 activity assay. Salvage experiment was also conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. Results. LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. A significant reversal of EMT was observed in LOXL2-silenced DU145 cells. Cell apoptosis after irradiation was significantly enhanced by LOXL2 knockdown in DU145 cells. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. Conclusions. LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Targeting LOXL2 may be a rational avenue to overcome radioresistance in CRPC cells. A LOXL2-targeting strategy for CRPC treatment warrants detailed investigation in the future.

Bradykinin-related compounds as new drugs for cancer and inflammation

2002 ◽  
Vol 80 (4) ◽  
pp. 275-280 ◽  
Author(s):  
John M Stewart ◽  
Lajos Gera ◽  
Daniel C Chan ◽  
Paul A Bunn Jr. ◽  
Eunice J York ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Nude Mice ◽  
Small Cell ◽  
Small Cell Lung ◽  
Related Compounds

Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Igl, α-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg·kg–1·day–1 beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg·kg–1, M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.Key words: bradykinin antagonists, cancer, inflammation, prostate cancer, small cell lung cancer.

scholarly journals Independence of HIF1a and androgen signaling pathways in prostate cancer

2019 ◽  
Author(s):  
Maxine GB Tran ◽  
Becky AS Bibby ◽  
Lingjian Yang ◽  
Franklin Lo ◽  
Anne Warren ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Promote Tumor Growth ◽  
Elevated Expression

AbstractAndrogen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

scholarly journals Exploring the Value of BRD9 as a Biomarker, Therapeutic Target and Co-Target in Prostate Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1794
Author(s):  
Nafisa Barma ◽  
Timothy C. Stone ◽  
Lina Maria Carmona Echeverria ◽  
Susan Heavey
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Therapeutic Target ◽  
Advanced Prostate Cancer ◽  
Signalling Pathways ◽  
Gleason Grade ◽  
Clinical Biomarkers ◽  
Prostate Cancer Treatments

Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterise BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA M.expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression, and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signalling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

scholarly journals B7-H3 Promotes Prostate Cancer Progression in Mice by Antagonizing Myeloid-Derived Suppressor Cell Apoptosis

2020 ◽  
Vol 19 ◽  
pp. 153303382097164
Author(s):  
Yunfen Zhou ◽  
Guangbo Zhang ◽  
Weijie Zhang ◽  
Xuedong Wei ◽  
Jianquan Hou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cancer Progression ◽  
Cell Apoptosis ◽  
Control Cell ◽  
Cancer Cell Line ◽  
Cancer Prognosis ◽  
Prostate Cancer Progression

Background: B7-H3 is an important immunomodulatory molecule, and clinical studies have confirmed that its expression level is closely correlated with prostate cancer prognosis. However, the mechanism of its biological action is unclear. Methods: An engineered cell line overexpressing B7-H3 was constructed. Cell apoptosis, growth and proliferation assays in vitro and an animal model in vivo were performed to analyze the role and possible mechanism of B7-H3 in promoting prostate cancer progression. Results: Compared with the control cell line (Mock-RM-1), the B7-H3-overexpressing prostate cancer cell line (B7-H3-RM-1) showed no significant growth differences in vitro, whereas the in vivo tumorigenesis rate of B7-H3-RM-1 was significantly higher than that of Mock-RM-1. These results suggest that B7-H3indirectly, rather than directly, promotes prostate cancer progression. Further analysis revealed that significantly higher levels of myeloid-derived suppressor cells (MDSCs) accumulated in vivo in B7-H3-RM-1 tumor-bearing mice than in Mock-RM-1 mice. In vitro and in vivo experiments showed that B7-H3-RM-1 cells significantly antagonized MDSC apoptosis. To further confirm the role of MDSCs in B7-H3-mediated prostate cancer progression, model mice were pretreated with cyclophosphamide before inoculation to clear immune cells and achieve myelo suppression. The results showed no significant differences in tumor growth between the B7-H3-RM-1 group and the Mock-RM-1 group. Conclusions: We found, for the first time, that B7-H3 can antagonize MDSC apoptosis, leading to MDSC accumulation in the tumor microenvironment and thereby promoting prostate cancer progression.

scholarly journals Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway

2018 ◽  
Vol 45 (3) ◽  
pp. 1121-1135 ◽  
Author(s):  
Hanzhang Zhu ◽  
Jingrui Wang ◽  
Junjie Yin ◽  
Bei Lu ◽  
Qijun Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Poor Prognosis ◽  
P53 Pathway ◽  
Tissue Samples ◽  
Potential Biomarker

Background/Aims: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. Methods: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. Results: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. Conclusions: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.

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