A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

Ilana Chefetz, Edward Grimley, Kun Yang, Linda Hong, Ekaterina V. Vinogradova, Radu Suciu, Ilya Kovalenko, David Karnak, Cynthia A. Morgan, Mikhail Chtcherbinine, Cameron Buchman, Brandt Huddle, Scott Barraza, Meredith Morgan, Kara A. Bernstein, Euisik Yoon, David B. Lombard, Andrea Bild, Geeta Mehta, Iris RomeroChun Yi Chiang, Charles Landen, Benjamin Cravatt, Thomas D. Hurley, Scott D. Larsen, Ronald J. Buckanovich

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 + ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.

Original languageEnglish
Pages (from-to)3061-3075.e6
JournalCell Reports
Volume26
Issue number11
DOIs
Publication statusPublished - 2019 Mar 12

Bibliographical note

Funding Information:
The work was supported by the U.S. Department of Defense (grant OC130322) and the NIH (grant 5R01CA214567). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG (CA014599) and Ovarian Cancer SPORE (grant P50CA046592) (to I.R.); NIH (R01-AA18123 and R21-CA198409) (to T.D.H.); NIH (R01GM101171) and U.S. Department of Defense (OC140123) (to D.B.L.); and NIH (ES024872) and SU2C (SU2C-AACR-IRG-02-16) (to K.A.B.).

Funding Information:
The work was supported by the U.S. Department of Defense (grant OC130322 ) and the NIH (grant 5R01CA214567 ). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG ( CA014599 ) and Ovarian Cancer SPORE (grant P50CA046592 ) (to I.R.); NIH ( R01-AA18123 and R21-CA198409 ) (to T.D.H.); NIH ( R01GM101171 ) and U.S. Department of Defense ( OC140123 ) (to D.B.L.); and NIH ( ES024872 ) and SU2C ( SU2C-AACR-IRG-02-16 ) (to K.A.B.).

Publisher Copyright:
© 2019 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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