Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Kokal, Miriam; Mirzakhani, Kimia; Pungsrinont, Thanakorn; Baniahmad, Aria

doi:10.3390/cancers12071833

Cited by 25 publications

(32 citation statements)

References 144 publications

(220 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Incidence of PCa in male population is high, and disease development predominantly depends on the androgen and androgen receptor (AR) signaling. 12 Mortality and morbidity of PCa are consistently increasing worldwide despite extensive use of a diagnostic marker, prostate-specific antigen (PSA). 13 Patients at the early stage of PCa can be effectively treated using the ADT approach 14 ; however, the majority of PCa patients will develop advanced PCa, namely, CRPC.…”

Section: Discussionmentioning

confidence: 99%

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation

Zheng

Gong

et al. 2021

The Prostate

View full text Add to dashboard Cite

Background: Prostate cancer (PCa) is a leading cause of death in men, and effective treatment of PCa requires further development. Our study aimed to investigate the potential role of vinculin (VCL) in PCa progression in vitro and in vivo. Methods: We investigated the methylation level of the VCL promoter based on the TCGA database. The knockdown efficacy of VCL gene expression was confirmed by quantitative polymerase chain reaction, Western blot analysis, and immunofluorescence. Furthermore, morphological changes in PCa cells were detected using phalloidin staining. The mobility of PCa cells was measured using transwell assays and high-content analysis. Moreover, cell growth and viability were determined using the colony formation and cell counting kit-8 assays. The role of VCL in tumor growth in vivo was investigated using a subcutaneous xenograft model generated by injecting tumor cells into the right flank of BALB/c nude mice. Results: The methylation level of the VCL promoter in PCa was significantly downregulated concomitant with age and the progression of nodal metastasis. VCL expression was markedly decreased by shRNA. Importantly, VCL knockdown significantly changed the cell morphology; inhibited the migration, invasion, and movement; and repressed colony formation and viability of PCa cells in vitro. Furthermore, downregulation of VCL suppressed tumor growth in vivo. Conclusions: Our study comprehensively evaluated the role of VCL in PCa progression in vivo and in vitro. The findings of the present study suggest that VCL can be a potential target for PCa prognosis and treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation

Zheng

Gong

et al. 2021

The Prostate

View full text Add to dashboard Cite

show abstract

“…Anti-androgen treatment is the first non-surgical treatment for PRAD (34). It has been shown that the level of the androgen receptor (AR) gene expression in tumor tissue is closely related to anti-androgen treatment sensitivity (35). Therefore, we also compared the expression levels of AR in the three subtypes and found that tumors from C1 and C3 had higher AR expression levels than those from C2 ( Figure 9A).…”

Section: Drug Sensibility Analysis With Metabolism-associated Subtypementioning

confidence: 99%

Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

Zhang

Liang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

BackgroundDespite being the second most common tumor in men worldwide, the tumor metabolism-associated mechanisms of prostate cancer (PCa) remain unclear. Herein, this study aimed to investigate the metabolism-associated characteristics of PCa and to develop a metabolism-associated prognostic risk model for patients with PCa.MethodsThe activity levels of PCa metabolic pathways were determined using mRNA expression profiling of The Cancer Genome Atlas Prostate Adenocarcinoma cohort via single-sample gene set enrichment analysis (ssGSEA). The analyzed samples were divided into three subtypes based on the partitioning around medication algorithm. Tumor characteristics of the subsets were then investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis, differential analysis, Kaplan–Meier survival analysis, and GSEA. Finally, we developed and validated a metabolism-associated prognostic risk model using weighted gene co-expression network analysis, univariate Cox analysis, least absolute shrinkage and selection operator, and multivariate Cox analysis. Other cohorts (GSE54460, GSE70768, genotype-tissue expression, and International Cancer Genome Consortium) were utilized for external validation. Drug sensibility analysis was performed on Genomics of Drug Sensitivity in Cancer and GSE78220 datasets. In total, 1,039 samples and six cell lines were concluded in our work.ResultsThree metabolism-associated clusters with significantly different characteristics in disease-free survival (DFS), clinical stage, stemness index, tumor microenvironment including stromal and immune cells, DNA mutation (TP53 and SPOP), copy number variation, and microsatellite instability were identified in PCa. Eighty-four of the metabolism-associated module genes were narrowed to a six-gene signature associated with DFS, CACNG4, SLC2A4, EPHX2, CA14, NUDT7, and ADH5 (p <0.05). A risk model was developed, and external validation revealed the strong robustness our risk model possessed in diagnosis and prognosis as well as the association with the cancer feature of drug sensitivity.ConclusionsThe identified metabolism-associated subtypes reflected the pathogenesis, essential features, and heterogeneity of PCa tumors. Our metabolism-associated risk model may provide clinicians with predictive values for diagnosis, prognosis, and treatment guidance in patients with PCa.

show abstract

“…Mechanistically, AR antagonists can induce cellular senescence in PCa cells in vitro as well as ex vivo in patients PCa samples. This indicates that AR antagonists do not completely inhibit the AR rather promote the induction of an AR-dependent cellular senescence pathway [ 11 , 12 , 13 ]. Although cellular senescence induces an irreversible cell cycle arrest being in general advantageous for PCa therapy, senescent cells show a senescence associated secretory phenotype that might induce cell proliferation within the tumor microenvironment including in neighboring non-senescent PCa cells.…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Ehsani

David

Baniahmad

2021

Cancers

Self Cite

View full text Add to dashboard Cite

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed.

show abstract

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Cited by 25 publications

References 144 publications

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation

Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Contact Info

Product

Resources

About