Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis
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nihms897190.pdf
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Author(s)
Tang, Yun-Chi
Yuwen, Hui
Wang, Kaiying
Bruno, Peter M.
Bullock, Kevin
Deik, Amy
Zhong, Na
Huang, Tao
Wang, Lan
Clish, Clary B.
Date Issued
January 2017
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Tang, Yun-Chi et al. “Aneuploid Cell Survival Relies Upon Sphingolipid Homeostasis.” Cancer Research 77, 19 (August 2017): 5272–5286 © 2017 American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-17-0049
