Research Papers:

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

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

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:6270-6281. https://doi.org/10.18632/oncotarget.23569

Metrics: PDF 1397 views  |   HTML 3178 views  |   ?  


Harman Chopra1,*, Zara Khan1,*, Jamie Contreras1,*, Herui Wang1, Abanob Sedrak1 and Yan Zhu1

1Department of Biological Sciences, St. John's University, Queens, NY 11439, USA

*These authors contributed equally to this work

Correspondence to:

Yan Zhu, email: [email protected]

Keywords: androgen receptor; p53; MDM2; MDMX; prostate cancer

Received: January 18, 2017     Accepted: October 13, 2017     Published: December 15, 2017


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23569