Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Jacob, Aasems; Raj, Rishi; Allison, Derek B.; Myint, Zin

doi:10.3390/cancers13215417

Cited by 58 publications

(62 citation statements)

References 119 publications

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“…Interestingly, these genes found in the glycolysis-related signature are predominantly associated with the androgen receptor. It is prominent that PCa is an androgen-dependent tumor, and AR is essential for the pathogenesis of PCa (51). In anabolic regulation, AR directly elevates key enzymes involved in glycolysis, including hexokinase I and II (HK1 and HK2) (52), suggesting that AR might also regulate the glycolysis-related signature identified in this study.…”

Section: Discussionmentioning

confidence: 63%

A combined signature of glycolysis and immune landscape predicts prognosis and therapeutic response in prostate cancer

Guo

Wang²,

Yan³

et al. 2022

Front. Endocrinol.

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Prostate cancer (PCa) is a common malignancy that poses a major threat to the health of men. Prostate-specific antigen (PSA) and its derivatives, as FDA-approved detection assays, are insufficient to serve as optimal markers for patient prognosis and clinical decision-making. It is widely acknowledged that aberrant glycolytic metabolism in PCa is related to tumor progression and acidifies the tumor microenvironment (TME). Considering the non-negligible impacts of glycolysis and immune functions on PCa, we developed a combined classifier in prostate cancer. The Glycolysis Score containing 19 genes and TME Score including three immune cells were created, using the univariate and multivariate Cox proportional hazards model, log-rank test, least absolute shrinkage and selection operator (LASSO) regression analysis and the bootstrap approach. Combining the glycolysis and immunological landscape, the Glycolysis-TME Classifier was then constructed. It was observed that the classifier was more accurate in predicting the prognosis of patients than the current biomarkers. Notably, there were significant differences in metabolic activity, signaling pathways, mutational landscape, immunotherapeutic response, and drug sensitivity among the Glycolysishigh/TMElow, Mixed group and Glycolysislow/TMEhigh identified by this classifier. Overall, due to the significant prognostic value and potential therapeutic guidance of the Glycolysis-TME Classifier, we anticipate that this classifier will be clinically beneficial in the management of patients with PCa.

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Section: Discussionmentioning

confidence: 63%

A combined signature of glycolysis and immune landscape predicts prognosis and therapeutic response in prostate cancer

Guo

Wang²,

Yan³

et al. 2022

Front. Endocrinol.

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show abstract

“…Several signaling pathways, including Wnt, TGF-β, PI3K/Akt, mTOR, and p38-MAPK pathways, have been reported to contribute to the emergence and growth of androgen-independent PCa (AIPC) with the crosstalk of AR pathways [ 12 , 13 ]. In order to explore the upstream signaling pathways that regulate RP11-1023L17.1 in AIPC, we evaluated the effect of signaling pathway inhibitors on RP11-1023L17.1 expression.…”

Section: Resultsmentioning

confidence: 99%

Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer

Huang

Chen

et al. 2022

IJMS

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Long noncoding RNAs (lncRNAs) have been found as novel participants in the pathophysiology of prostate cancer (PCa), which is predominantly regulated by androgen and its receptor. The biological function of androgen-responsive lncRNAs remains poorly understood. Here, we identified that lncRNA RP11-1023L17.1, which is highly expressed in PCa. RP11-1023L17.1 expression, can be directly repressed by the androgen receptor in PCa cells. RP11-1023L17.1 depletion inhibited the proliferation, migration, and cell cycle progression, and promoted the apoptosis of PCa cells, indicating that RP11-1023L17.1 acts as an oncogene in PCa cells. Microarray results revealed that RP11-1023L17.1 depletion downregulated the c-Myc transcription signature in PCa cells. RP11-1023L17.1 depletion-induced cellular phenotypes can be overcome by ectopically overexpressed c-Myc. Mechanistically, RP11-1023L17.1 represses FBXO32 mRNA expression, thereby enhancing c-Myc protein stability by blocking FBXO32-mediated c-Myc degradation. Our findings reveal the previously unrecognized roles of RP11-1023L17.1 in c-Myc-dependent PCa tumorigenesis.

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“…L702H, T878A, H875Y, W742C, and W743L are the most prevalent mutations reported in clinical prostate cancer patients (Fig. 3) [74,75]. These point mutations in the LBD may result in lower AR antagonist binding affinity or even conversion of the AR antagonist into an agonist.…”

Section: Emerging Mechanisms Of Resistance To Ar Antagonists Ar Alter...mentioning

confidence: 99%

“…3 Recurrent AR mutations and alternative splicing variants contribute to AR antagonist resistance. Mutations in red are the most prevalent mutations in patients [74,75], while those in black are enzalutamide-and apalutamide-resistant mutations [76,77]. AR-v7 lacks exons 4/5/6/7/8 and differs by 16aa at the C-terminus compared with AR-FL.…”

Section: Reprogramming Of Ar Transcriptional Activity By Ar Antagonistsmentioning

confidence: 99%

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

et al. 2022

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Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

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Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Cited by 58 publications

References 119 publications

A combined signature of glycolysis and immune landscape predicts prognosis and therapeutic response in prostate cancer

A combined signature of glycolysis and immune landscape predicts prognosis and therapeutic response in prostate cancer

Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

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