Skip to main content

Local navigation

Metabolism and signaling

Application in studying metabolic responses to different DNA damaging agents in breast cancer cells

Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking.
We used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADPribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DDRs.
Our findings indicate that cancer cell metabolic responses depend on the type of DDRs and can also be used to classify the type of DNA damage.

Metabolic responses to DNA damaging agents

The figure shows the metabolic profiles in response to different drug treatments in MCF7 cell line. a) Principal component analysis, b) hierarchical clustering and c) Pathway topology analysis to identify enriched pathways in reponse to different drug treatments. (Figure modified from Bhute, Vijesh J., and Sean P. Palecek. "Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells." Metabolomics 11.6 (2015): 1779-1791.)