title: Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells.
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.
authors.affiliation: Departments of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhou
authors.forename: Federico
authors.initials: F
authors.lastname: Tozzi
authors.forename: Jinyu
authors.initials: J
authors.lastname: Chen
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.forename: Jinrong
authors.initials: J
authors.lastname: Wang
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xia
authors.forename: Heather
authors.initials: H
authors.lastname: Brasher
authors.forename: William
authors.initials: W
authors.lastname: Widger
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000255:Adenosine Triphosphate
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