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. Wiktorowicz & 2 others Robert L. Coleman, Anil K. Sood

    Research output: Contribution to journalArticle

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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

    Fingerprint

    Ovarian Neoplasms
    Topotecan
    Mitochondria
    Cell Death
    Neoplasms
    Cell Nucleus Active Transport
    Paclitaxel
    Tumor Burden
    Proteomics
    Cytoplasm
    Breast
    Research Design
    Therapeutics
    Breast Neoplasms
    Drug Therapy
    Cell Line
    Pharmaceutical Preparations

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Miyake, T., Pradeep, S., Wu, S. Y., Rupaimoole, R., Zand, B., Wen, Y., ... 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

    XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A. / Miyake, Takahito; Pradeep, Sunila; Wu, Sherry Y.; Rupaimoole, Rajesha; Zand, Behrouz; Wen, Yunfei; Gharpure, Kshipra M.; Nagaraja, Archana S.; Hu, Wei; Cho, Min Soon; Dalton, Heather J.; Previs, Rebecca A.; Taylor, Morgan L.; Hisamatsu, Takeshi; Kang, Yu; Liu, Tao; Shacham, Sharon; McCauley, Dilara; Hawke, David H.; Wiktorowicz, John E.; Coleman, Robert L.; Sood, Anil K.

    In: Clinical Cancer Research, Vol. 21, No. 14, 15.07.2015, p. 3286-3297.

    Research output: Contribution to journalArticle

    Miyake, T, Pradeep, S, Wu, SY, Rupaimoole, R, Zand, B, Wen, Y, Gharpure, KM, Nagaraja, AS, Hu, W, Cho, MS, Dalton, HJ, Previs, RA, Taylor, ML, Hisamatsu, T, Kang, Y, Liu, T, Shacham, S, McCauley, D, Hawke, DH, Wiktorowicz, JE, Coleman, RL & Sood, AK 2015, 'XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A', Clinical Cancer Research, vol. 21, no. 14, pp. 3286-3297. https://doi.org/10.1158/1078-0432.CCR-14-1953
    Miyake, Takahito ; Pradeep, Sunila ; Wu, Sherry Y. ; Rupaimoole, Rajesha ; Zand, Behrouz ; Wen, Yunfei ; Gharpure, Kshipra M. ; Nagaraja, Archana S. ; Hu, Wei ; Cho, Min Soon ; Dalton, Heather J. ; Previs, Rebecca A. ; Taylor, Morgan L. ; Hisamatsu, Takeshi ; Kang, Yu ; Liu, Tao ; Shacham, Sharon ; McCauley, Dilara ; Hawke, David H. ; Wiktorowicz, John E. ; Coleman, Robert L. ; Sood, Anil K. / XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 14. pp. 3286-3297.
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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.",
    author = "Takahito Miyake and Sunila Pradeep and Wu, {Sherry Y.} and Rajesha Rupaimoole and Behrouz Zand and Yunfei Wen and Gharpure, {Kshipra M.} and Nagaraja, {Archana S.} and Wei Hu and Cho, {Min Soon} and Dalton, {Heather J.} and Previs, {Rebecca A.} and Taylor, {Morgan L.} and Takeshi Hisamatsu and Yu Kang and Tao Liu and Sharon Shacham and Dilara McCauley and Hawke, {David H.} and Wiktorowicz, {John E.} and Coleman, {Robert L.} and Sood, {Anil K.}",
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    T1 - XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A

    AU - Miyake, Takahito

    AU - Pradeep, Sunila

    AU - Wu, Sherry Y.

    AU - Rupaimoole, Rajesha

    AU - Zand, Behrouz

    AU - Wen, Yunfei

    AU - Gharpure, Kshipra M.

    AU - Nagaraja, Archana S.

    AU - Hu, Wei

    AU - Cho, Min Soon

    AU - Dalton, Heather J.

    AU - Previs, Rebecca A.

    AU - Taylor, Morgan L.

    AU - Hisamatsu, Takeshi

    AU - Kang, Yu

    AU - Liu, Tao

    AU - Shacham, Sharon

    AU - McCauley, Dilara

    AU - Hawke, David H.

    AU - Wiktorowicz, John E.

    AU - Coleman, Robert L.

    AU - Sood, Anil K.

    PY - 2015/7/15

    Y1 - 2015/7/15

    N2 - 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.

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