Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression

Abstract

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.

Differential tissue expression of extracellular vesicle‐derived proteins in prostate cancer

“…Administration of selective inhibitors of nuclear transport (SINE) such as Selinexor, have led to an enrichment of tumor suppressor proteins in the nucleus . This subsequently resulted in apoptosis, reduction of tumor spreading and improved overall survival in preclinical models in PCa . Clinical studies are being performed to reveal the real potential of XPO1‐directed therapy.…”

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

“…PNET cell lines were seeded in 60-mm petri dishes. The next day cells were treated with single-agent KPT-9274, analogs, everolimus, INK128, or their combination at the indicated concentrations and incubated for 72 h. After the treatment period, cells were washed with PBS, trypsinized and stained with Annexin V and Propidium Iodide (Annexin V FITC) [41] or 7-AAD viability staining solution (7-AAD) [42]. Stained cells were sorted using the Becton Dickinson flow cytometer at the Karmanos Cancer Institute Flow Cytometry Core.…”

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“…In previous studies, increased expression of XPO1 in prostate cancer was associated with high Gleason scores and an elevated risk of bone metastases [7]. In the current study, Aboukameel et al demonstrated that increased expression of XPO1 was associated with higher AR-V7 levels, that disruption of XPO1 (through RNA interference or pharmacologic inhibition using SINE compounds: selinexor and eltanexor) inhibited expression of AR and AR-V7 together with abrogation of their transcriptional programs, and that inhibition of XPO1 in vitro and in vivo in AR-V7expressing cell lines and xenograft models (either using SINE agents alone or in combination with abiraterone and enzalutamide) restricted tumor growth [5]. The authors concluded that XPO1 inhibition by selinexor or eltanexor might represent a promising treatment strategy for the management of human CRPC.…”