Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis
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.; Hemann, Michael T.; Santaguida, Stefano; Trakala, Marianna; Pfau, Sarah Jeanne; Amon, Angelika B; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
American Association for Cancer Research (AACR)
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)
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