XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells

Abstract

Previous work has shown that the three‐dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT‐185, KPT‐330/selinexor, and KPT‐8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment‐naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non‐lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. J. Cell. Physiol. 231: 2711–2719, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

“…Exportin-1 (XPO-1), also known as chromosomal region maintenance 1 (CRM1), shuttles about 220 proteins from the nucleus to the cytoplasm [ 17 , 18 ] and is the sole nuclear exporter of several tumor suppressor (TSP) and growth regulatory (GRP) proteins, such as p53 and p73 [ 19 , 20 ], p21 [ 21 ], survivin [ 22 , 23 ], cyclin D1 [ 23 , 24 ], Rb1 [ 25 ], apc [ 26 ], bcr-abl [ 27 ], FOXO [ 28 ], p27 [ 29 ] and STAT3 [ 30 ]. Physiologically, export of these proteins prevents unnecessary activity in the absence of DNA injury and other oncogenic activities [ 31 – 33 ]. In tumor cells, however, the export of these proteins inhibits their activity thus promoting tumorigenesis.…”

Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition

“…We further determined if TChal bound to the sulfhydryl group of Cys 528 in CRM1 as previously shown with leptomycin B [ 30 ]; however, TChal was found to not bind to the same site on CRM1 as leptomycin B (data not shown). Since the clinical development of leptomycin B has been limited by its toxicity and narrow therapeutic window in preclinical animal models, orally bioavailable small-molecule selective inhibitors of nuclear export (SINEs) that specifically and irreversibly bind to residue Cys 528 in the cargo-binding groove of CRM1 have been developed and tested with positive outcomes [ 44 ]. Thus, TChal may be another CRM1 inhibitor that exhibits anti-CRM1 activity with less side effects.…”

Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells

“…The sequestration of some XPO1 cargos, the functions of some proteins, and gross cell fates after treatment with SINE indicate that nuclear export is blocked rapidly and the cell responses are highly complex [ 6 , 10 , 20 , 34 ]. For example, recent studies document decreased ribosome biogenesis [ 35 ], disrupted nuclear architecture of telomeres [ 36 ], synthetic lethality with oncogenic K-Ras [ 20 ], and NFκB/IκB regulation after treatment with SINE [ 34 ].…”