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

Publication ,  Journal Article
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 ...
Published in: Clin Cancer Res
July 15, 2015

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 15, 2015

Volume

21

Issue

14

Start / End Page

3286 / 3297

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transfection
  • Tandem Mass Spectrometry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Signal Transduction
  • Receptors, Cytoplasmic and Nuclear
  • RNA-Binding Proteins
  • RNA, Small Interfering
  • Proteomics
  • Peptide Initiation Factors
 

Citation

APA
Chicago
ICMJE
MLA
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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. Clin Cancer Res, 21(14), 3286–3297. https://doi.org/10.1158/1078-0432.CCR-14-1953
Miyake, Takahito, Sunila Pradeep, Sherry Y. Wu, Rajesha Rupaimoole, Behrouz Zand, Yunfei Wen, Kshipra M. Gharpure, et al. “XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A.Clin Cancer Res 21, no. 14 (July 15, 2015): 3286–97. https://doi.org/10.1158/1078-0432.CCR-14-1953.
Miyake T, Pradeep S, Wu SY, Rupaimoole R, Zand B, Wen Y, et al. XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A. Clin Cancer Res. 2015 Jul 15;21(14):3286–97.
Miyake, Takahito, et al. “XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A.Clin Cancer Res, vol. 21, no. 14, July 2015, pp. 3286–97. Pubmed, doi:10.1158/1078-0432.CCR-14-1953.
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. XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A. Clin Cancer Res. 2015 Jul 15;21(14):3286–3297.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 15, 2015

Volume

21

Issue

14

Start / End Page

3286 / 3297

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transfection
  • Tandem Mass Spectrometry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Signal Transduction
  • Receptors, Cytoplasmic and Nuclear
  • RNA-Binding Proteins
  • RNA, Small Interfering
  • Proteomics
  • Peptide Initiation Factors