CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: Molecular mechanisms and therapeutic implications

Y. T. Tai, Y. Landesman, C. Acharya, Y. Calle, M. Y. Zhong, M. Cea, D. Tannenbaum, A. Cagnetta, M. Reagan, A. A. Munshi, W. Senapedis, J. R. Saint-Martin, T. Kashyap, S. Shacham, M. Kauffman, Y. Gu, L. Wu, I. Ghobrial, F. Zhan, A. L. KungS. A. Schey, P. Richardson, N. C. Munshi, K. C. Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED 50 κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalLeukemia
Volume28
Issue number1
DOIs
Publication statusPublished - 2014

Keywords

  • multiple myeloma (MM)
  • nuclear export protein
  • nuclear factor-B (NF- B) activation
  • osteoclasts (OC)
  • selective inhibitors of nuclear export (SINEs) against CRM1/XPO1
  • tumor suppressors

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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