Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Abstract

A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

“…Selinexor-induced apoptosis could be explained in part by the significant induction of the proapoptotic proteins BIM and BAX, which are not directly regulated by XPO1 but transcriptionally controlled by XPO1 cargoes such as p53 and/or FOXO3a proteins (4,7,19,20). Interestingly, p53 and FOXO3a appeared to be differently needed for selinexor cytotoxicity in different cell lines, a likely reflection of different statuses of p53/FOXO3a and/or of their networking molecules in the cells.…”

“…Notably, about 20% human TETs harbor p53 inactivating mutations, indicating the importance of p53 loss in TET pathogenesis (21)(22)(23). Unlike p53, the tumor suppressor activity of FOXO3a could be diminished by other mechanisms, for instance, overactivation of the PI3K-AKT pathway, which causes XPO1-dependent cytoplasmic entrapment of FOXO3a (4,7). It is clear, however, that the antitumor activity of selinexor in TETs may depend on p53, FOXO3a, and/or other XPO1 cargo proteins, even though p53 seems to be particularly important in most cases.…”

“…We then examined the effect of XPO1 inhibition on the nuclear-cytoplasmic shuttling of several known XPO1 cargo proteins (7). Selinexor treatment resulted in a significant shift in the balance of FOXO3a, p53, and p27 proteins in the nucleus and cytoplasm, leading to nuclear accumulation of these TSPs ( Fig.…”

“…1), two important TSPs that control the expression of many crucial genes and regulate various key cellular processes (4,7). To definitively demonstrate the contribution of these two TSPs to the antitumor activity of selinexor, we assessed the viability of TET cells treated with selinexor after siRNA knockdown of p53 and/or FOXO3a.…”

“…Latterly developed small-molecule selective inhibitors of nuclear export (SINE) represent a different class of XPO1 inhibitors with better specificity and efficacy. Selinexor (KPT-330) is one of such SINE compounds that is currently in clinical development (4,7,8). Unlike LMB that forms an irreversible covalent bond with cysteine-528 residue located in the vicinity of LR-NES-binding domain in XPO1, selinexor binds XPO1 through the same residue in a covalent but slowly reversible manner (4).…”