Abstract
Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.
Highlights
Liposarcoma is the most common type of softtissue tumor, accounting for 24% of extremity and 45% retroperitoneal soft-tissue sarcomas [1,2,3]
Our study showed that selinexor treatment restored tumor suppressive function of insulin-like growth factor binding protein 5 (IGFBP5) and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer
To examine the biological role of XPO1 in liposarcoma, the gene was first suppressed using shRNA targeting to XPO1 resulted in 70–90% silencing of XPO1 protein in liposarcoma cells (LPS141, SW872, MLS402 and SA4) compared to scramble shRNA as shown by western blot analysis (Figure 1E)
Summary
Liposarcoma is the most common type of softtissue tumor, accounting for 24% of extremity and 45% retroperitoneal soft-tissue sarcomas [1,2,3]. Leptomycin B was the first well known natural XPO1 inhibitor that suppressed the growth of several human cancer cell lines [20] This drug had significant toxicity and a narrow therapeutic window in preclinical animal models, as well as in phase 1 human clinical trial [21]. Phase I/II human clinical trials have indicated that selinexor is well-tolerated and has a favorable outcome in patients with either relapsed or refractory acute myeloid leukemia (NCT01607892) and solid tumors (NCT01607905, NCT01896505) [22] (www.clinicaltrials.gov). In this current study, therapeutic potential of selinexor was examined against liposarcoma both in cell culture and in a murine xenograft model. Selinexor significantly inhibited cellular proliferation and induced cell cycle arrest and apoptosis of liposarcoma both in vitro and in vivo
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