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Title: Iron addiction: a novel therapeutic target in ovarian cancer

Abstract

Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Some mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). Here, we show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [8];  [10];  [11];  [12];  [1]
  1. Univ. of Connecticut Health Center, Formington, CT (United States). Dept. of Molecular Biology and Biophysics
  2. National Cancer Center Research Inst., Tokyo (Japan)
  3. Jackson Lab. for Genomic Medicine, Farmington, CT (United States)
  4. Univ. of Texas Health Center, Houston, TX (United States). Center for Stem Cells and Regenerative Medicine
  5. Univ. of Houston, TX (United States). Dept. of Biology and Biochemistry
  6. Univ. of Connecticut Health Center, Farmington, CT (United States). Center for Quantitative Medicine
  7. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States). Dept. of Pathology
  8. Univ. of Connecticut Health Center, Farmington, CT (United States). Dept. of Pathology
  9. Univ. of Connecticut Health Center, Farmington, CT (United States). Dept. of Obstetrics and Gynecology
  10. Wake Forest School of Medicine, Winston-Salem, NC (United States). Dept. of Cancer Biology
  11. Univ. of Connecticut Health Center, Farmington, CT (United States). Reconstructive Sciences
  12. Univ. of Connecticut Health Center, Farmington, CT (United States). Dept. of Medicine
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1412859
Report Number(s):
LA-UR-17-20000
Journal ID: ISSN 0950-9232; TRN: US1800377
Grant/Contract Number:
AC52-06NA25396; R01 CA188025; R01 CA171101
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Oncogene
Additional Journal Information:
Journal Volume: 36; Journal Issue: 29; Journal ID: ISSN 0950-9232
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Biological Science; ovarian cancer iron metabolism

Citation Formats

Basuli, D., Tesfay, L., Deng, Z., Paul, B., Yamamoto, Y., Ning, G., Xian, W., McKeon, F., Lynch, M., Crum, C. P., Hegde, P., Brewer, M., Wang, X., Miller, L. D., Dyment, N., Torti, F. M., and Torti, S. V. Iron addiction: a novel therapeutic target in ovarian cancer. United States: N. p., 2017. Web. doi:10.1038/onc.2017.11.
Basuli, D., Tesfay, L., Deng, Z., Paul, B., Yamamoto, Y., Ning, G., Xian, W., McKeon, F., Lynch, M., Crum, C. P., Hegde, P., Brewer, M., Wang, X., Miller, L. D., Dyment, N., Torti, F. M., & Torti, S. V. Iron addiction: a novel therapeutic target in ovarian cancer. United States. doi:10.1038/onc.2017.11.
Basuli, D., Tesfay, L., Deng, Z., Paul, B., Yamamoto, Y., Ning, G., Xian, W., McKeon, F., Lynch, M., Crum, C. P., Hegde, P., Brewer, M., Wang, X., Miller, L. D., Dyment, N., Torti, F. M., and Torti, S. V. Mon . "Iron addiction: a novel therapeutic target in ovarian cancer". United States. doi:10.1038/onc.2017.11. https://www.osti.gov/servlets/purl/1412859.
@article{osti_1412859,
title = {Iron addiction: a novel therapeutic target in ovarian cancer},
author = {Basuli, D. and Tesfay, L. and Deng, Z. and Paul, B. and Yamamoto, Y. and Ning, G. and Xian, W. and McKeon, F. and Lynch, M. and Crum, C. P. and Hegde, P. and Brewer, M. and Wang, X. and Miller, L. D. and Dyment, N. and Torti, F. M. and Torti, S. V.},
abstractNote = {Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Some mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). Here, we show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.},
doi = {10.1038/onc.2017.11},
journal = {Oncogene},
number = 29,
volume = 36,
place = {United States},
year = {Mon Mar 20 00:00:00 EDT 2017},
month = {Mon Mar 20 00:00:00 EDT 2017}
}

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