Abstract
Breast tumors are characterized into subtypes based on their surface marker expression, which affects their prognosis and treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. Here, we used NMR-based metabolomics to probe cell line-specific effects of the PARP inhibitor Veliparib and radiation on metabolism in three breast cancer cell lines. Our data reveal several cell line-independent metabolic changes upon PARP inhibition. Pathway enrichment and topology analysis identified that nitrogen metabolism, glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis and taurine and hypotaurine metabolism were enriched after PARP inhibition in all three breast cancer cell lines. Many metabolic changes due to radiation and PARP inhibition were cell line-dependent, highlighting the need to understand how these treatments affect cancer cell response via changes in metabolism. Finally, both PARP inhibition and radiation induced a similar metabolic responses in BRCA-mutant HCC1937 cells, but not in MCF7 and MDAMB231 cells, suggesting that radiation and PARP inhibition share similar interactions with metabolic pathways in BRCA mutant cells. Our study emphasizes the importance of differences in metabolic responses to cancer treatments in different subtypes of cancers.
Highlights
Cancer metabolism plays an important role in every stage of tumor pathology[14] and some of the earliest discoveries that identified differences between tumor and healthy cells involved differences in metabolism of glucose
Radiation induced significant changes in HCC1937 cells which were similar to Poly (ADP-ribose) polymerase (PARP) inhibition (PI) relative to control
PI led to increased NAD+ concentration, which correlated with a decrease in creatine concentration, in MCF7 and MDAMB231 cells
Summary
Cancer metabolism plays an important role in every stage of tumor pathology[14] and some of the earliest discoveries that identified differences between tumor and healthy cells involved differences in metabolism of glucose (e.g., the Warburg effect[15]). In a previous study[18], we identified several metabolic changes in MCF7 breast cancer cells in response to Veliparib (ABT-888), a potent PARPi, as well as radiation. These included significantly higher levels of NAD+, glutamine, myo-inositol, taurine, and sn-glycero-3-phosphocholine (GPC), and significantly lower levels of lactate, alanine, pyruvate, phosphocreatine after one day of PARPi treatment. We sought to identify the cell line-independent effects of PARP inhibition (PI) on cancer cell metabolism and compare these effects with the metabolic responses elicited by radiation. Our data suggest significant cell line-dependent effects on metabolism due to PARP inhibition and radiation in breast cancer cells
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