Therapeutics , Targets , and Chemical Biology Intracellular ATP Levels Are a Pivotal Determinant of Chemoresistance in Colon Cancer Cells

Alteredmetabolism in cancer cells is suspected to contribute to chemoresistance, but the precise mechanisms are unclear. Here, we show that intracellular ATP levels are a core determinant in the development of acquired cross-drug resistance of human colon cancer cells that harbor different genetic backgrounds. Drug-resistant cells were characterized by defectivemitochondrial ATP production, elevated aerobic glycolysis, higher absolute levels of intracellular ATP, and enhanced HIF-1a–mediated signaling. Interestingly, direct delivery of ATP into crosschemoresistant cells destabilizedHIF-1a and inhibited glycolysis. Thus, drug-resistant cells exhibit a greater "ATP debt" defined as the extra amount of ATP needed to maintain homeostasis of survival pathways under genotoxic stress. Direct delivery of ATP was sufficient to render drug-sensitive cells drug resistant. Conversely, depleting ATP by cell treatment with an inhibitor of glycolysis, 3-bromopyruvate, was sufficient to sensitize cells crossresistant to multiple chemotherapeutic drugs. In revealing that intracellular ATP levels are a core determinant of chemoresistance in colon cancer cells, our findingsmay offer a foundation for new improvements to colon cancer treatment. Cancer Res; 72(1); 304–14. 2011 AACR.