XPO1 Inhibition by Selinexor Induces Nuclear p53 and p21 Accumulation, Cell-Cycle Arrest and Apoptosis in Testicular Germ Cell Tumors

Testicular germ cell tumors (TGCTs) are the most prevalent solid malignancies in young men. Despite effective cisplatin-based chemotherapy, resistance and long-term toxicities persist. Selinexor, an FDA-approved XPO1 inhibitor, exhibited potential anti-tumor activity in other cancers, but its effects on TGCTs were unexplored. This study aimed to determine the impact of selinexor on TGCT cell lines.

The researchers measured XPO1 RNA expression, protein abundance, and localization via immunohistochemistry in TGCT tissue microarrays, non-neoplastic testicular tissues, and publicly available gene-expression microarray datasets encompassing normal testis, primary TGCT specimens, and TGCT cell lines. They assessed selinexor's effects on cell viability, cell-cycle distribution, and apoptosis using the XTT assay and flow cytometry.

Additionally, they analyzed p53 and p21 expression and localization through Western blotting and immunofluorescence.

Results indicated that XPO1 expression varied across normal testis, TGCT tissues, and cell lines. Nevertheless, selinexor diminished TGCT cell viability, induced G1 or G2/M cell-cycle arrest, triggered apoptosis, and elevated total p53 and p21 protein levels. Importantly, p53 and p21 proteins accumulated in the nucleus. Control fibroblast cells displayed limited sensitivity to selinexor. The findings suggest that inhibiting XPO1 with selinexor could potentially serve as a therapeutic strategy for TGCTs.