Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

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.

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…Selinexor treatment showed decreased cellular growth as well as induced cell cycle arrest and apoptosis of liposarcoma cells in vitro, which was independent of p53 expression or mutational status [52,54] . Further, oral administration of selinexor led to significant decrease in the tumor growth and increased in apoptosis of liposarcoma cells in a xenograft murine model which was associated with decreased staining of Ki-67, CD31and increased staining of TUNEL [52,54] . Interestingly, selinexor treatment increased the expression of insulin-like growth factor binding protein 5 (IGFBP5) in liposarcoma cells and suppressed the phosphorylation of both IGF-1R and AKT in an IGF-1 dependent manner [52] .…”

“…Further, oral administration of selinexor led to significant decrease in the tumor growth and increased in apoptosis of liposarcoma cells in a xenograft murine model which was associated with decreased staining of Ki-67, CD31and increased staining of TUNEL [52,54] . Interestingly, selinexor treatment increased the expression of insulin-like growth factor binding protein 5 (IGFBP5) in liposarcoma cells and suppressed the phosphorylation of both IGF-1R and AKT in an IGF-1 dependent manner [52] . Growth inhibitory effect of selinexor treatment was partially rescued by silencing of IGFBP5 in liposarcoma cells and concluded that IGFBP5 act as tumor suppressor in liposarcoma.…”

“…Liposarcoma is the most common type of soft tissue sarcoma with a high recurrence rate and less responsive to available therapies [51,52] . To date, complete surgical is the best therapeutic option.…”

“…Most of the patients have tumors recurrence and metastasis after surgery, which is associated with a high mortality rate [51,53] . Recently, we showed that XPO1 protein was overexpressed in different histological subtypes of liposarcoma in patient samples than benign lipoma as well as normal fat [52] . Selinexor treatment showed decreased cellular growth as well as induced cell cycle arrest and apoptosis of liposarcoma cells in vitro, which was independent of p53 expression or mutational status [52,54] .…”

“…Recently, we showed that XPO1 protein was overexpressed in different histological subtypes of liposarcoma in patient samples than benign lipoma as well as normal fat [52] . Selinexor treatment showed decreased cellular growth as well as induced cell cycle arrest and apoptosis of liposarcoma cells in vitro, which was independent of p53 expression or mutational status [52,54] . Further, oral administration of selinexor led to significant decrease in the tumor growth and increased in apoptosis of liposarcoma cells in a xenograft murine model which was associated with decreased staining of Ki-67, CD31and increased staining of TUNEL [52,54] .…”