Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells

Olson, Brian M.; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin J.; Ellis, Leigh; Drake, Charles G.; Weichert, Jamey P.; McNeel, Douglas G.

doi:10.1158/2326-6066.cir-16-0390

Cited by 28 publications

(22 citation statements)

References 48 publications

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“…Considering that androgens and ARs are valuable targets of PCa treatment, and that their therapeutic benefit is somewhat limited by autophagy, our preliminary studies suggest that autophagy modulation might further improve malignant biological behavior, such as apoptosis and tumor growth, but have no influence on invasion and metastasis (Culig and Santer 2014;Olson et al 2017).…”

Section: Discussionmentioning

confidence: 96%

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

Wang

Duan

et al. 2020

All Life

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2020) MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgendependent human prostate cancer, All Life, 13:1, 171-182, ABSTRACTWe proposed that autophagy activated through PPARγ in prostate cancer could protect cancer against androgen deprivation. Our MTT and western blotting assay results showed that mimics of miR-337-3p repressed autophagy flux under androgen deprivation, whereas inhibitors had the opposite effect. Neither mimics nor inhibitors influenced cell motility and invasion. miR-337-3p downregulated PPARγ expression in dual luciferase reporter assays and promoted AMPK phosphorylation. The overexpression of PPARγ or AMPK agonists partly diminished the adverse influence of mimics on proliferation and cell autophagy. In a mouse xenograft model, tumors transplanted with LNCap cells having a miR-337-3p deficiency had a significantly larger volume and lower rate of apoptosis than in controls after orchidectomy. Our findings showed that the negative effects of miR-337-3p on cell survival after androgen deprivation through PPARγ degeneration and modulated autophagy could serve as a novel therapeutic target for androgen-dependent prostate cancer and provide a strategy against resistance to anti-androgen therapy. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 96%

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

Wang

Duan

et al. 2020

All Life

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“…Interestingly, WWTR1 and YAP1_PS127 both belong to the Hippo signaling pathway, and they are frequently hyperactivated in cancer (57). For the proteins that increased with ERRα/ABCC4 alteration, AR (androgen receptor) is expressed in primary and metastatic PCa, and downregulation of AR is considered a potential therapy for PCa (58,59). CHEK2 is a gene involved in DNA repair and its mutation is associated with PCa (60).…”

Section: Discussionmentioning

confidence: 99%

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Huang

Shen

et al. 2020

Front. Oncol.

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Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

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“…From a slightly different perspective, a study by Olson et al showed that prostate cancer cells express higher levels of AR upon androgen deprivation, which in turn improves recognition of tumor cells by AR-specific T cells ( 144 , 145 ). Therefore, direct targeting of the AR could be a promising immunotherapeutic approach.…”

Section: The Role Of Androgens In Anti-cancer Immune Therapymentioning

confidence: 99%

Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer

et al. 2020

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It is well-known that sex hormones can directly and indirectly influence immune cell function. Different studies support a suppressive role of androgens on different components of the immune system by decreasing antibody production, T cell proliferation, NK cytotoxicity, and stimulating the production of anti-inflammatory cytokines. Androgen receptors have also been detected in many different cells of hematopoietic origin leading to direct effects of their ligands on the development and function of the immune system. The immunosuppressive properties of androgens could contribute to gender dimorphisms in autoimmune and infectious disease and thereby also hamper immune surveillance of tumors. Consistently, females generally are more prone to autoimmunity, while relatively less susceptible to infections, and have lower incidence and mortality of the majority of cancers compared to males. Some studies show that androgen deprivation therapy (ADT) can induce expansion of naïve T cells and increase T-cell responses. Emerging clinical data also reveal that ADT might enhance the efficacy of various immunotherapies including immune checkpoint blockade. In this review, we will discuss the potential role of androgens and their receptors in the immune responses in the context of different diseases. A particular focus will be on cancer, highlighting the effect of androgens on immune surveillance, tumor biology and on the efficacy of anti-cancer therapies including emerging immune therapies.

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Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells

Cited by 28 publications

References 48 publications

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer

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