Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

The Journal of Biological Chemistry
Renee C GeckAlex Toker

Abstract

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well...Continue Reading

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Citations

Jul 30, 2020·Cancers·Amandine Moretton, Joanna I Loizou
Aug 24, 2020·Bioorganic & Medicinal Chemistry·Bartlomiej BorekRoman Blaszczyk
Oct 16, 2020·Trends in Immunology·Elisa ProiettiGiada Mondanelli
Aug 3, 2021·BioMed Research International·Haiping DuanDongfeng Zhang
Sep 17, 2021·Breast Cancer Research and Treatment·Caleb C CapellenSurabhi Chandra

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