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Cancer Res. 2012 Jan 1;72(1):304-14. doi: 10.1158/0008-5472.CAN-11-1674. Epub 2011 Nov 14.

Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells.

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  • 1Departments of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230, USA.

Abstract

Altered metabolism 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 defective mitochondrial ATP production, elevated aerobic glycolysis, higher absolute levels of intracellular ATP, and enhanced HIF-1α-mediated signaling. Interestingly, direct delivery of ATP into cross-chemoresistant cells destabilized HIF-1α 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 cross-resistant to multiple chemotherapeutic drugs. In revealing that intracellular ATP levels are a core determinant of chemoresistance in colon cancer cells, our findings may offer a foundation for new improvements to colon cancer treatment.

©2011 AACR.

PMID:
22084398
[PubMed - indexed for MEDLINE]
PMCID:
PMC3601736
Free PMC Article
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