PT  - JOURNAL ARTICLE
AU  - Renee C. Geck
AU  - Jackson R. Foley
AU  - Tracy R. Murray Stewart
AU  - John M. Asara
AU  - Robert A. Casero, Jr.
AU  - Alex Toker
TI  - Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy
AID  - 10.1101/2020.01.08.899492
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.08.899492
4099  - http://biorxiv.org/content/early/2020/01/09/2020.01.08.899492.short
4100  - http://biorxiv.org/content/early/2020/01/09/2020.01.08.899492.full
AB  - Treatment of triple-negative breast cancer (TNBC) is limited by a lack of effective molecular targeted therapies. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. We found that exposure of TNBC cells to cytotoxic chemotherapy drugs leads to alterations in arginine and polyamine metabolites due to a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase (ODC). The reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor DFMO sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines showed greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. Alterations in polyamine metabolism in response to chemotherapy, as well as preferential sensitization of TNBC cells to chemotherapy by DFMO, suggest that ODC may be a targetable metabolic vulnerability in TNBC.ARG2Arginase 2ASS1Argininosuccinate SynthaseAZIantizyme inhibitor (protein)AZINantizyme inhibitor (gene/transcript)CDDPcisplatinDFMOα-difluoromethylornithineDOXOdoxorubicinNOHANω-hydroxy-nor-arginineOAZ1antizyme 1 (gene/transcript)ODCOrnithine DecarboxylasePBTpolyamine blocking therapySAMS-adenosyl methionineArgL-arginineOrnornithinePutputrescineSAMS-adenosyl-L-methionineSpmspermineSpdspermidineTNBCtriple-negative breast cancer