Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants

Shiota, Masaki; Dejima, Takashi; Yamamoto, Yoshiaki; Takeuchi, Ario; Imada, Kenjiro; Kashiwagi, Eiji; Inokuchi, Junichi; Tatsugami, Katsunori; Kajioka, Shunichi; Uchiumi, Takeshi; Eto, Masatoshi

doi:10.1111/cas.13751

Cited by 21 publications

(26 citation statements)

References 56 publications

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“…AR V7 is known to promote cellular resistance to ARAT agents, and possibly to taxanes . Based on these findings, cellular sensitivities to enzalutamide and docetaxel were examined.…”

Section: Resultsmentioning

confidence: 99%

“…This study showed that TSC exposure was involved in cellular resistance to anticancer agents. It is reported that expression of AR variants renders prostate cancer cells resistant to taxanes . Meanwhile, AR variants are known to be critical factors affecting cellular sensitivity to ARAT agents, including enzalutamide .…”

Section: Discussionmentioning

confidence: 99%

“…RNA isolation and reverse transcription were performed as described previously . Quantitative real‐time PCR was performed using TaqMan Gene Expression Assays (Thermo Fisher Scientific) for full‐length AR (Hs00171172_m1), AR V7 (order‐made), and GAPDH (Hs02758991_g1), and TaqMan Gene Expression Master Mix (Thermo Fisher Scientific) on a CFX Connect Real‐Time System (Bio‐Rad, Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

“…The cell proliferation assay was performed as described previously . 22Rv1 cells (2.5 × 10 4 ) were seeded in 12‐well plates.…”

Section: Methodsmentioning

confidence: 99%

“…2.3 | RNA isolation, reverse transcription, and quantitative real-time PCR RNA isolation and reverse transcription were performed as described previously. [17][18][19][20] Quantitative real-time PCR was performed using TaqMan Gene Expression Assays (Thermo Fisher Scientific) for full-length AR (Hs00171172_m1), AR V7 (ordermade), and GAPDH (Hs02758991_g1), and TaqMan Gene Expression Master Mix (Thermo Fisher Scientific) on a CFX Connect Real-Time System (Bio-Rad, Hercules, CA). The transcript levels of target genes were corrected by the corresponding GAPDH transcript levels.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

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Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy

et al. 2019

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Background Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. Methods Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real‐time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR‐axis‐targeting (ARAT) agent enzalutamide and docetaxel. Results Expression of AR variants as well as prostate‐specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N‐acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression‐free survival and cancer‐specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. Conclusions It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.

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“…AR V7 is known to promote cellular resistance to ARAT agents, and possibly to taxanes . Based on these findings, cellular sensitivities to enzalutamide and docetaxel were examined.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The cell proliferation assay was performed as described previously . 22Rv1 cells (2.5 × 10 4 ) were seeded in 12‐well plates.…”

Section: Methodsmentioning

confidence: 99%

Section: Antibodies and Reagentsmentioning

confidence: 99%

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Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy

et al. 2019

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Preclinical Models of Neuroendocrine Prostate Cancer

et al. 2023

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Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer‐related death amongst men in the United States. Neuroendocrine prostate cancer (NEPC) can either arise de novo or emerge as a consequence of therapy. De novo NEPC is rare, with an incidence of <2% of all PCa cases. In contrast, treatment‐induced NEPC is frequent with >20% of patients with metastatic castration‐resistant prostate cancer (CRPC) reported to progress to neuroendocrine (NE) differentiation. The emergence of treatment‐induced NEPC is linked to the increased therapeutic pressure, due to the broad application of androgen deprivation therapy (ADT) for PCa management and the development of novel more potent androgen receptor (AR) pathway inhibitors. NEPC is a high‐grade tumor type characterized by aggressive phenotype and clinical behavior. Patients affected by NEPC frequently develop visceral metastases and have a poor prognosis. The molecular mechanisms underlying the development and progression of NEPC are still poorly understood. Transcriptional and epigenetic reprogramming appears to be involved in NE progression. In this review, we aim to provide a comprehensive view of the available models for NEPC detailing their strengths and limitations. Moreover, we describe novel approaches to expand the repertoire of preclinical models to better study, prevent, or reverse NEPC. The integration of multiple preclinical models along with molecular and omics approaches will provide important insights to understand disease progression and to devise novel therapeutic strategies for the management of NEPC in the near future. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of organoids starting from the prostate gland of a GEMM or a human PDX Basic Protocol 2: Ex vivo tumor sphere formation

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High‐throughput screen identifies 5‐HT receptor as a modulator of AR and a therapeutic target for prostate cancer

et al. 2020

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BackgroundEradication of persistent androgen receptor (AR) activity in castration‐resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer.MethodsA high‐throughput screening system involving cell lines stably expressing AR protein and AR‐responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR.ResultsThe high‐throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5‐hydroxytryptamine 5A (5‐HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5‐HT5A receptor knockdown. Consistently, 5‐HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells.ConclusionsTaken together, this study identifies 5‐HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.

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Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants

Cited by 21 publications

References 56 publications

Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy

Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy

Preclinical Models of Neuroendocrine Prostate Cancer

High‐throughput screen identifies 5‐HT receptor as a modulator of AR and a therapeutic target for prostate cancer

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