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

Authors :
David H. Hawke
John E. Wiktorowicz
Sharon Shacham
Archana S. Nagaraja
Morgan Taylor
Rebecca A. Previs
Kshipra M. Gharpure
Sherry Y. Wu
Dilara McCauley
Robert L. Coleman
Heather J. Dalton
Rajesha Rupaimoole
Behrouz Zand
Tao Liu
Yu Kang
Takeshi Hisamatsu
Anil K. Sood
Takahito Miyake
Sunila Pradeep
Yunfei Wen
Min Soon Cho
Wei Hu
Publication Year :
2015

Abstract

Purpose: XPO1 inhibitors have shown promise for cancer treatment, and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1. Experimental Design: We used proteomic analysis in XPO1 inhibitor–treated ovarian cancer cell lines and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents. Results: XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO independent. Significant antitumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (P < 0.001) and breast (P < 0.001) cancer mouse models, with a further decrease in tumor burden observed in combination with topotecan or paclitaxel (P < 0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels. Conclusions: We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor–mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials. Clin Cancer Res; 21(14); 3286–97. ©2015 AACR.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....204db2c4b331280881982ddaa30c2e61