TRIM36, a novel androgen-responsive gene, enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathways

Chao Liang,Shangqian Wang,Chao Qin,Zengjun Wang,Min Gu,Jie Li,Qiang Lv,Gong Cheng,Meilin Bao,Lixin Hua,Pengfei Shao,Bianjiang Liu,Ninghong Song

doi:10.1038/s41419-017-0197-y

Chao Liang, Shangqian Wang + Show 11 more

Open Access

https://doi.org/10.1038/s41419-017-0197-y

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Abstract

Hormone therapy drugs, such as bicalutamide and enzalutamide, directed against prostate cancer focus on androgen receptor (AR) signaling and are initially effective, but the disease progresses to lethality as resistance to these drugs develops. A method to prolong the drug response time and improve the drug efficacy is still unavailable. TRIM36 was reported as a novel androgen signaling target gene and is upregulated in prostate cancer. In this study, we found that 63.4% (64/95) of PCa in TMA expressed the TRIM36 protein. Interestingly, patients with negative TRIM36 expression had a shorter biochemical recurrence-free survival. TRIM36 expression was significantly associated with the Gleason score (P = 0.005), delayed prostate cancer cell cycle progression and inhibited cell proliferation in vitro and in vivo, and these effects were mediated via inhibition of the MAPK/ERK phosphorylation pathway. Remarkably, we found that rescuing the expression of TRIM36 during anti-androgen therapy could improve the drug efficacy. Collectively, TRIM36 is a novel androgen-responsive gene, and it dramatically enhanced the efficacy of anti-androgen drugs against prostate cancer.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and prospectively accounts for 19% of cancer diagnoses in 2017 despite recent rapid declines[1]
TRIM36 over-expression has been observed in PCa tissues[18], and this observation was confirmed in our previous microarray data (Fig. 1a)
The impressive effect of androgen deprivation therapy (ADT) with anti-androgen treatments to prevent androgens from binding to the Androgen receptor (AR) identified by Huggins and Hodges in 1941 was of paramount significance in prostate cancer[2]

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and prospectively accounts for 19% of cancer diagnoses in 2017 despite recent rapid declines[1]. Androgen receptor (AR) signaling plays a critical role in tumorigenesis and the development of PCa, and androgen deprivation therapy (ADT) has been used as a standard treatment for patients with advanced prostate cancer[2]. ADT is initially effective for patients with hormone-sensitive metastatic prostate cancer, long-term treatment invariably results in the progression to lethal castration-resistant prostate cancer (CRPC)[3]. Enzalutamide will once again block AR action in CRPC, and AR action is the key master that influences PCa progression. These findings validate the concept that the AR pathway is a central target for drug therapy[5,6,7,8,9]

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Results

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