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XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A

Takahito Miyake1, Sunila Pradeep1, Sherry Y Wu1

  • 1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 17, 2015
PubMed
Abstract

Insights

Selective inhibitors of nuclear export (SINE) compounds targeting XPO1 induce cancer cell death by promoting mitochondrial eIF5A accumulation. This mechanism shows promise for ovarian and breast cancer treatments, especially in combination with chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Selective inhibitors of nuclear export (SINE) compounds targeting XPO1 are promising cancer therapeutics.
  • The precise mechanisms underlying their antitumor effects remain largely unelucidated.
  • Understanding these pathways is crucial for optimizing their clinical application.

Purpose of the Study:

  • To investigate the molecular mechanisms by which XPO1 inhibitors exert antitumor effects.
  • To explore the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cancer cell death.
  • To evaluate the efficacy of XPO1 inhibitors as monotherapy and in combination with chemotherapeutic agents.

Main Methods:

  • Proteomic analysis was performed on ovarian cancer cell lines treated with XPO1 inhibitors.
  • Antitumor effects were assessed in ovarian and breast cancer mouse models.
  • Synergistic effects with chemotherapeutic agents were investigated.

Main Results:

  • XPO1 inhibition significantly increased apoptosis (60% at 72 hours) and promoted eIF5A mitochondrial accumulation, leading to cancer cell death.
  • XPO1 inhibitors prevented IGF2BP1 nuclear-to-cytoplasmic translocation, facilitating eIF5A mitochondrial localization, independent of p53, RB, and FOXO.
  • Significant antitumor activity was observed in ovarian and breast cancer models, with enhanced efficacy when combined with topotecan or paclitaxel.

Conclusions:

  • A novel mechanism of XPO1 inhibitor-mediated cell death involving eIF5A and IGF2BP1 has been identified.
  • These findings support the clinical development of XPO1 inhibitors for ovarian and other cancers.
  • Specific combinations of XPO1 inhibitors with chemotherapy drugs are recommended for future therapeutic trials.

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