Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells.

Harman Chopra,Herui Wang,Yan Zhu,Zara Khan,Abanob Sedrak,Jamie Contreras

doi:10.18632/oncotarget.23569

Abstract

Castration-resistant prostate cancer (CRPC) frequently develops after initial standard radiation and androgen deprivation therapy, leaving patients with limited further treatment options. Androgen receptor (AR) is a transcription factor that plays a key role in the initiation and progression of prostate cancer. p53, a major tumor suppressor that is rarely mutated in early-stages of prostate cancer, is often deregulated during prostate cancer progression. Here, we report an unusual co-amplification of MDM2 and MDMX, two crucial negative regulators of p53, in CRPC datasets. We demonstrate that combinatorial inhibition of MDM2 and MDMX, with nutlin-3 and NSC207895 respectively, has a profound inhibitory effect on cell proliferation of androgen-responsive, wild-type TP53 gene carrying prostate cancer cells LNCaP and 22Rv1. We further show that the combinatorial inhibition of MDM2 and MDMX not only activates p53, but also decreases cellular levels of AR and represses its function. Additionally, co-expression of MDM2 and MDMX stabilizes AR. Together, our results indicate that combinatorial inhibition of MDM2 and MDMX may offer a novel compelling strategy for prostate cancer therapy.

Highlights

Prostate cancer is the most common cancer in men [1]
To test the hypothesis that combined inhibition of MDM2 and MDMX suppresses cell growth of prostate cancer cells, we examine the effect of various MDM2/MDMX inhibitors (Supplementary Figure 2) on cell proliferation of three different prostate cancer cell lines (Figure 2A): LNCaP cells are responsive to androgen and contain the wild-type p53 gene. 22Rv1 cells are partially responsive to androgen and contain one wild-type copy of p53 and one mutated copy of p53
Overexpression of MDM2 has been linked to advanced stages of prostate cancer, the role of MDMX in prostate cancer progression remains unclear

Summary

Introduction

Prostate cancer is the most common cancer in men [1]. Since majority of patients progress to castrationresistant prostate cancer (CRPC) with limited treatment options [2,3,4], new therapies are urgently needed. Prostate cancer initiation and progression are uniquely dependent on the androgen receptor (AR), a hormone-inducible DNA-binding transcription factor that plays a critical role in the development and function of the prostate [5, 6]. Overexpression of MDM2 and MDMX is often mutually exclusive in cancer cells [29], suggesting that dysregulation of either one of the inhibitors is sufficient for p53 inactivation, leading to tumor development. Because the TP53 gene often remains wild-type in MDM2- or MDMX-overexpressing cancers, it has long been thought that targeting MDM2 or MDMX could restore p53 activity for cancer therapy [28, 30, 31]. P53 activation has been found to augment the antitumor outcome of androgen ablation in prostate cancer [32]

Methods

Results

Conclusion