Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: The role of survivin

Michelandrea de Cesare, Denis Cominetti, Valentina Doldi, Alessia Lopergolo, Marcello Deraco, Paolo Gandellini, Sharon Friedlander, Yosef Landesman, Michael G. Kauffman, Sharon Shacham, Marzia Pennati, Nadia Zaffaroni

Research output: Contribution to journalArticle

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 antitumor 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.

Original languageEnglish
Pages (from-to)13119-13132
Number of pages14
JournalOncotarget
Volume6
Issue number15
DOIs
Publication statusPublished - 2015

Fingerprint

Cell Nucleus Active Transport
Neoplasms
Ubiquitination
G1 Phase
Proteasome Endopeptidase Complex
Caspases
Nuclear Proteins
Cell Cycle Checkpoints
Malignant Mesothelioma
Heterografts
Cell Survival
Cytoplasm
Cell Proliferation
Apoptosis
Growth
exportin 1 protein

Keywords

  • Diffuse malignant peritoneal mesothelioma
  • SINE
  • Survivin
  • XPO1/CRM1

ASJC Scopus subject areas

  • Oncology

Cite this

Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma : The role of survivin. / de Cesare, Michelandrea; Cominetti, Denis; Doldi, Valentina; Lopergolo, Alessia; Deraco, Marcello; Gandellini, Paolo; Friedlander, Sharon; Landesman, Yosef; Kauffman, Michael G.; Shacham, Sharon; Pennati, Marzia; Zaffaroni, Nadia.

In: Oncotarget, Vol. 6, No. 15, 2015, p. 13119-13132.

Research output: Contribution to journalArticle

de Cesare, M, Cominetti, D, Doldi, V, Lopergolo, A, Deraco, M, Gandellini, P, Friedlander, S, Landesman, Y, Kauffman, MG, Shacham, S, Pennati, M & Zaffaroni, N 2015, 'Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: The role of survivin', Oncotarget, vol. 6, no. 15, pp. 13119-13132. https://doi.org/10.18632/oncotarget.3761
de Cesare, Michelandrea ; Cominetti, Denis ; Doldi, Valentina ; Lopergolo, Alessia ; Deraco, Marcello ; Gandellini, Paolo ; Friedlander, Sharon ; Landesman, Yosef ; Kauffman, Michael G. ; Shacham, Sharon ; Pennati, Marzia ; Zaffaroni, Nadia. / Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma : The role of survivin. In: Oncotarget. 2015 ; Vol. 6, No. 15. pp. 13119-13132.
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