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

Oncotarget
Harman ChopraYan Zhu

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.

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Citations

Feb 7, 2019·Cancer Biotherapy & Radiopharmaceuticals·Abdulhameed Al-Ghabkari, Aru Narendran
Jan 29, 2019·Journal of Molecular Cell Biology·Sue HauptYgal Haupt
May 1, 2021·Cancers·Giovana de Godoy FernandesCarlos Eduardo Fonseca-Alves
Aug 27, 2021·Journal of Extracellular Vesicles·Elena S Martens-UzunovaCarolina Soekmadji
Sep 24, 2021·Nature·Haitham A ElmarakebyEliezer M Van Allen

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Datasets Mentioned

BETA
GSE35988

Methods Mentioned

BETA
ubiquitination
RNA-seq
PCR
transfection
immunoprecipitation
Assay

Software Mentioned

cBioPortal
Gene Set Enrichment Analysis ( GSEA
Image J
GEO2R
MeV
CompuSyn

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