Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression
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Amro Aboukameel1, Irfana Muqbil2, Erkan Baloglu3, William Senapedis3, Yosef Landesman3, Christian Argueta3, Michael Kauffman3, Hua Chang3, Trinayan Kashyap3, Sharon Shacham3, Jasper E. Neggers4, Dirk Daelemans4, Elisabeth I. Heath1 and Asfar S. Azmi1
1Wayne State University School of Medicine, Detroit, MI, USA
2University of Detroit Mercy, Detroit, MI, USA
3Karyopharm Therapeutics Inc, Newton, MA, USA
4KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat, Belgium
Elisabeth I. Heath, email: firstname.lastname@example.org
Asfar S. Azmi, email: email@example.com
Keywords: metastatic prostate cancer; AR SPLICE variant; nuclear export; CRM1; SINE
Received: July 12, 2018 Accepted: October 06, 2018 Published: October 19, 2018
Emerging studies have shown that the expression of AR splice variants (ARv) lacking ligand-binding domain is associated with castrate-resistant prostate cancer (CRPC) and higher risk of tumor metastasis and recurrence. Nuclear export protein XPO1 regulates the nuclear localization of many proteins including tumor suppressor proteins. Increased XPO1 in prostate cancer is associated with a high Gleason score and bone metastasis. In this study, 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 eltanexor (KPT-8602) down-regulated the expression of AR, AR-v7 and ARv567es at mRNA and protein levels. XPO1 silencing also inhibited the expression of AR and ARv regulators including FOXA1, Src, Vav3, MED1 and Sam68, leading to the suppression of ARv and AR target genes, UBE2C and PSA. By targeting XPO1/ARv signaling, SINE suppressed prostate cancer (PCa) growth in vitro and in vivo and potentiated the anti-cancer activity of anti-AR agents, enzalutamide and abiraterone. Therefore, XPO1 inhibition could be a novel promising agent used in combination with conventional chemotherapeutics and AR-targeted therapy for the better treatment of PCa, especially CRPC.
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