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

Yunfei Zhou, Federico Tozzi, Jinyu Chen, Fan Fan, Ling Xia, Jinrong Wang, Guang Gao, Aijun Zhang, Xuefeng Xia, Heather Brasher, William Widger, Lee M. Ellis, Zhang Weihua

Research output: Contribution to journalArticlepeer-review

210 Scopus citations

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-1aand 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.

Original languageEnglish (US)
Pages (from-to)304-314
Number of pages11
JournalCancer Research
Volume72
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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