Abstract
Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM.
Highlights
Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and locally aggressive tumor that develops from mesothelial cells lining the peritoneal cavity, and accounts for approximately 25–30% of all mesotheliomas [1, 2]
While the low molecular weight of survivin allows its passive diffusion from the cytoplasm to the nucleus, its export from the nucleus back to the cytoplasm requires an interaction between the exportin-1/chromosome maintenance protein 1 (XPO1/CRM1) and the specific leucine-rich nuclear export signals (NES) within survivin
While STO cells showed a higher sensitivity to selinexor compared to KPT-251 and KPT-276, with inhibit cell growth by 50% (IC50) values of 0.07 ± 0.01, 0.23 ± 0.05 and 0.24 ± 0.02 μmol/L respectively, MesoII cells showed a comparable sensitivity to all the compounds with IC50 values of 0.35 ± 0.09, 0.36 ± 0.04 and 0.47 ± 0.04 μmol/L, respectively
Summary
Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and locally aggressive tumor that develops from mesothelial cells lining the peritoneal cavity, and accounts for approximately 25–30% of all mesotheliomas [1, 2]. The advent of a loco-regional strategy that combines aggressive cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) [3,4] significantly improved median survival up to 40–92 months in selected series of patients, approximately 40–60% of patients still experience recurrence [3,4,5] For these patients, and for those who are not eligible to CRS+HIPEC, the prognosis remains www.impactjournals.com/oncotarget severe due to the lack of effective alternative treatment options, highlighting the need to develop new therapeutic strategies. While the low molecular weight of survivin allows its passive diffusion from the cytoplasm to the nucleus, its export from the nucleus back to the cytoplasm requires an interaction between the exportin-1/chromosome maintenance protein 1 (XPO1/CRM1) and the specific leucine-rich nuclear export signals (NES) within survivin. XPO1/ CRM1 is a key member of the importin β superfamily of nuclear transport receptors that are involved in the nucleo-cytoplasmic active transport of over 200 proteins, including transcription factors, tumor suppressors, cellcycle regulators and proteins involved in programmed cell death [10, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
