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

• Published in: The Journal of biological chemistry Vol. 295; no. 19; pp. 6263 - 6277
• Main Authors: Geck, Renee C., Foley, Jackson R., Murray Stewart, Tracy, Asara, John M., Casero, Robert A., Toker, Alex
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2020; American Society for Biochemistry and Molecular Biology
• Subjects: amino acid; antizyme; Biogenic Polyamines - biosynthesis; breast cancer; Cell Line, Tumor; cell metabolism; Cytotoxins - pharmacology; difluoromethylornithine; DNA damage; Editors' Picks; Eflornithine - pharmacology; Female; Humans; metabolomics; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; ornithine decarboxylase (ODC); Ornithine Decarboxylase - metabolism; Ornithine Decarboxylase Inhibitors - pharmacology; polyamine; Proteasome Endopeptidase Complex - metabolism; Proteins - metabolism; Proteolysis - drug effects; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; triple-negative breast cancer (TNBC); polyamine; triple-negative breast cancer (TNBC); amino acid; metabolomics; DNA damage; ornithine decarboxylase (ODC); breast cancer; cell metabolism; antizyme; difluoromethylornithine
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.012376

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 as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.