Abstract 5953: Regulation of androgen receptor stability by nuclear export protein CRM1

Abstract

Abstract Import of ligand-bound androgen receptor (AR) into the nucleus occurs with the help of nuclear importin. Past studies have identified a nuclear export signal (NES) in AR. CRM1 (also called XPO1 or Exportin1) is a well-studied exportin that exports proteins and RNA from the nucleus to the cytoplasm. GTP-bound active Ran, CRM1, and the cargo protein form a ternary complex that is exported through the nuclear pore complex. Previous experimental data indicate that RanGTP plays a vital role in Prostate cancer (PCa) progression. Our analyses further suggest that patients who have overexpression of CRM1 and/or Ran have significantly decreased survival. These results indicate that nucleocytoplasmic transport is essential for prostate cancer progression and inhibiting CRM1 could selectively inhibit cancer cell growth. We demonstrate that CRM1 does not affect the nuclear export of AR protein. However, quite surprisingly, we provide novel evidence that CRM1 binds to AR mRNA and is also required for AR protein stability. Inhibiting CRM1 using CRM1 inhibitor results in a dose-dependent rapid loss of AR and AR-V7 splice variants in PCa cells. This observation opens up an entirely new avenue to therapeutically regulate AR signaling using CRM1 inhibitors. Citation Format: Naiju Thomas, Rajendra Kumar, Deven Topiwala, Kavya Boyapati, Suthicha Kanacharoen, Michael Carducci, Samuel Denmeade, Sushant K. Kachhap. Regulation of androgen receptor stability by nuclear export protein CRM1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5953.