Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression

Kameyama, Koji; Horie, Kengo; Mizutani, Kosuke; Kato, Taku; Fujita, Yasunori; Kawakami, Kyojiro; Kojima, Toshio; Miyazaki, Tatsuhiko; Deguchi, Takashi; Ito, Masafumi

doi:10.3892/ijo.2016.3781

Cited by 25 publications

(27 citation statements)

References 34 publications

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“…Using cell viability or colony formation assays, androgens have been shown to induce the growth of AR-positive bladder cancer cells [ 39 , 45 , 79 , 80 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Accordingly, AR knockdown as well as treatment with AR antagonists inhibited the cell proliferation of bladder cancer lines cultured with androgens.…”

Section: Role Of Ar Signaling In Urothelial Cancer Progressionmentioning

confidence: 99%

Androgen Receptor Signaling in Bladder Cancer

Chen

Miyamoto

2017

Cancers

104

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Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

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Section: Role Of Ar Signaling In Urothelial Cancer Progressionmentioning

confidence: 99%

Androgen Receptor Signaling in Bladder Cancer

Chen

Miyamoto

2017

Cancers

104

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“…An increasing number of studies have demonstrated that the aberrant expression of AR is a major factor that contributes to progression in many cancers, including breast, oral squamous cell, hepatocellular, bladder and GC by promoting tumor cell growth, but few studies have focused on metastasis [5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor variant 12 promotes migration and invasion by regulating MYLK in gastric cancer

Xia

Cui

Zhu

et al. 2019

The Journal of Pathology

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Androgen receptor (AR) and its variants (AR‐Vs) promote tumorigenesis and metastasis in many hormone‐related cancers, such as breast, prostate and hepatocellular cancers. However, the expression patterns and underlying molecular mechanisms of AR in gastric cancer (GC) are not fully understood. This study aimed to detect the expression of AR‐Vs in GC and explored their role in metastasis of GC. Here, the AR expression form was identified in GC cell lines and tissues by RT‐PCR and qPCR. Transwell assays and experimental lung metastasis animal models were used to assess the function of AR in cell migration and invasion. Downstream targets of AR were screened by bioinformatics, and identified by luciferase reporter assays and electrophoretic mobility shift assays. AR‐v12 was identified as the main expression form in GC cell lines and tissues. Different from full length of AR, AR‐v12 was localized to the nucleus independent of androgen. Upregulation of AR‐v12 in primary GC tissues was significantly associated with metastasis. Overexpression of AR‐v12 promoted migration and invasion independent of androgen. Knockdown of AR‐v12 inhibited migration and invasion in vitro, as well as metastasis in vivo. Furthermore, AR‐v12, serving as a transcription factor, promoted metastasis through regulating the promoter activity of MYLK. In AR‐v12 overexpressing cells, knockdown of MYLK inhibited cell migration and invasion, while in AR‐v12 knocked‐down cells, overexpression of MYLK promoted cell migration and invasion. Collectively, our study demonstrates that AR‐v12 is highly expressed in GC tissues and promotes migration and invasion through directly regulating MYLK. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC; refs. [2][3][4][5][6]. AR signaling has been reported to promote progression in RCC via the HIF-2a/VEGF signaling pathway, by recruiting vascular endothelial cells (5), and by altering the AKT/NFkB signaling axis (7).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma

et al. 2018

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Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array, we discovered increased expression of AR in an RCC patient-derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2. Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in a RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC. These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors. .

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Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression

Cited by 25 publications

References 34 publications

Androgen Receptor Signaling in Bladder Cancer

Androgen Receptor Signaling in Bladder Cancer

Androgen receptor variant 12 promotes migration and invasion by regulating MYLK in gastric cancer

Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma

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