Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.
Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
Xu
Rui-Hua
RH
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Pelicano
Helene
H
Zhou
Yan
Y
Carew
Jennifer S
JS
Feng
Li
L
Bhalla
Kapil N
KN
Keating
Michael J
MJ
Huang
Peng
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011773:Pyruvates; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C017092:bromopyruvate; D000255:Adenosine Triphosphate