Metabolic activation triggered by cAMP in MCF-7 cells generates lethal vulnerability to combined oxamate/etomoxir.

Background: Altered energy metabolism is a biochemical fingerprint of cancer cells, widely recognized as one of the "hallmarks of cancer". Cancer cells show highly increased rates of glucose uptake and glycolysis, after which the resulting pyruvate is converted to lactate. The maintenance of this metabolic asset is warranted by lactate dehydrogenase A (LDH-A) and for this reason the development of novel LDH-targeted anticancer therapeutics is underway. However, possible interference in cancer cell metabolism could also arise from cAMP signaling pathway, which could be activated by either oncogenic induction or exogenously, as a result of microenvironment-derived stimuli, increasing cellular cAMP levels. This study aimed at evaluating the impact of activated cAMP signaling pathway on the efficacy of an LDH-targeted anticancer approach.

Methods: We exogenously activated cAMP signaling in MCF-7 human breast cancer cells and explored the metabolic interplay between LDH-A and cAMP pathway.

Results: In cAMP-activated cells, we evidenced changes in energy metabolism which reduced their response to LDH inhibition. Interestingly, these experiments also highlighted a potential vulnerability state of treated cells.

Conclusions: cAMP-induced metabolic changes made MCF-7 cells a preferential target of a drug combination treatment which should not affect normal cell viability.

General Significance: cAMP is a well-recognized second messenger of the pro-inflammatory cascade. The obtained results are relevant in consideration of the crucial role played by inflammation in normal breast cell transformation and in cancer progression. Furthermore, they corroborate the idea of exploiting the metabolic changes observed in cancer cells to obtain a therapeutic advantage.