XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A

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

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    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 eIF5Awas 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.

    Original languageEnglish (US)
    Pages (from-to)3286-3297
    Number of pages12
    JournalClinical Cancer Research
    Volume21
    Issue number14
    DOIs
    StatePublished - Jul 15 2015

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    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Miyake, T., Pradeep, S., Wu, S. Y., Rupaimoole, R., Zand, B., Wen, Y., Gharpure, K. M., Nagaraja, A. S., Hu, W., Cho, M. S., Dalton, H. J., Previs, R. A., Taylor, M. L., Hisamatsu, T., Kang, Y., Liu, T., Shacham, S., McCauley, D., Hawke, D. H., ... Sood, A. K. (2015). XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A. Clinical Cancer Research, 21(14), 3286-3297. https://doi.org/10.1158/1078-0432.CCR-14-1953