Background: Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men. Despite high cure rates with cisplatin-based chemotherapy, resistance and long-term toxicities remain clinical challenges in TGCTs. Selinexor, an FDA-approved XPO1 inhibitor, has demonstrated anti-tumor activity in other cancers, but its potential in TGCTs remains unknown. Objective: We investigated the antitumor effects of selinexor in TGCT cell lines. Materials and methods: XPO1 RNA expression, protein abundance and localization were evaluated by immunohistochemistry in TGCT tissue microarrays and non-neoplastic testicular tissues, and by meta-analysis of publicly available gene-expression microarray datasets from normal testis, primary TGCT specimens as well as TGCT cell lines. Selinexor effects on cell viability, cell-cycle distribution and apoptosis were evaluated using XTT assay and flow cytometry. p53 and p21 expression and localization were analyzed by Western blotting and Immunofluorescence. Results: XPO1 expression was heterogeneous across normal testis, TGCT tissues and cell lines. Yet, selinexor reduced TGCT cell viability and induced G1 or G2/M cell-cycle arrest, apoptosis, increased total p53 and p21 protein levels, and their nuclear accumulation. Of note, control fibroblast exhibited limited sensitivity to selinexor. Discussion and conclusion: Our findings demonstrate that inhibition of XPO1 with selinexor might be potential therapeutic strategy for TGCTs.
Islam, R., Wladhaus, A., Bollen, I., Descher, L., Shalan, A., Balde, V. A. A., Liesen, A., Kovacevic, A., Merges, G. E., Kristiansen, G., Schorle, H.
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