Abstract 2492: Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression
Authors: Irfana Muqbil, Yiwei Li, Erkan Baloglu, William Senapedis, Yosef Landesman, Christian Argueta, Michael Kauffman, Sharon Friedlander, Hua Chang, Sharon Shacham, Elisabeth Heath, Asfar S. Azmi
Journal: Cancer Research (2018)

Abstract Increased XPO1 (a key nuclear exporter of many tumor suppressor proteins [TSPs]) expression in prostate cancer (PCa) has been found to be associated with a high Gleason score and bone metastasis. However, it is unknown whether aberrant XPO1 activity regulates AR and AR splice variants (Arv) signaling in PCa progression. In this study, using 22Rv1 and VCaP prostate cancer cells which harbor full length AR and ARv, we conduct in vitro cellular and molecular biological experiments and in vivo animal studies to elucidate the role XPO1 inhibition plays in PCa progression through regulation of XPO1/AR/ARv signaling. We found that high expression of AR splice variant 7 (AR-v7) was correlated with increased XPO1 expression. Silencing of XPO1 by RNAi or treatment with Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and KPT-8602/eltanexor) down-regulated the expression of AR, AR-v7 and ARv567es at the mRNA and protein levels. Mechanistic studies showed that XPO1 silencing also inhibited the expression of AR/ARv regulators including FOXA1, Src, Vav3, MED1 and Sam68, leading to the suppression of ARv and AR target genes, UBE2C and PSA. SINE compound treatment of cells retained the eIF4E protein (translation initiation factor and nuclear transporter of capped depended mRNAs) in nuclear compartment, leading to nuclear retention of AR-v7 and PSA mRNAs. The nuclear localization of AR-v7 mRNA resulted in the reduction in the ARv protein. Furthermore, SINE compound treatment retained TSPs including Rb, p21, p53, APC and SMAD4 in the nucleus leading to inhibition of cell proliferation and induction of apoptosis. Moreover, by targeting XPO1/ARv signaling, SINE compounds suppressed prostate cancer growth in vitro and in vivo and potentiated the anti-cancer activity of conventional chemotherapeutic agent docetaxel and anti-AR agents (enzalutamide and abiraterone) through the inhibition of AR, AR-v7, FOXA1, PSA and UBE2C. From these results, we conclude that there is a causal relationship between XPO1 and AR splice variants. High expression of both XPO1 and AR-v7 could lead to constitutively activated AR signaling, CRPC development and progression, and anti-AR drug resistance. By targeting XPO1/AR/ARv signaling and increasing anti-AR sensitivity, SINE compounds could be novel agents used in combination with conventional chemotherapeutics and AR-targeted therapy for the treatment of PCa, especially CRPC. Citation Format: Irfana Muqbil, Yiwei Li, Erkan Baloglu, William Senapedis, Yosef Landesman, Christian Argueta, Michael Kauffman, Sharon Friedlander, Hua Chang, Sharon Shacham, Elisabeth Heath, Asfar S. Azmi. Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2492.