title: Tumor cells switch to mitochondrial oxidative phosphorylation under radiation via mTOR-mediated hexokinase II inhibition--a Warburg-reversing effect.
abstract: A unique feature of cancer cells is to convert glucose into lactate to produce cellular energy, even under the presence of oxygen. Called aerobic glycolysis [The Warburg Effect] it has been extensively studied and the concept of aerobic glycolysis in tumor cells is generally accepted. However, it is not clear if aerobic glycolysis in tumor cells is fixed, or can be reversed, especially under therapeutic stress conditions. Here, we report that mTOR, a critical regulator in cell proliferation, can be relocated to mitochondria, and as a result, enhances oxidative phosphorylation and reduces glycolysis. Three tumor cell lines (breast cancer MCF-7, colon cancer HCT116 and glioblastoma U87) showed a quick relocation of mTOR to mitochondria after irradiation with a single dose 5 Gy, which was companied with decreased lactate production, increased mitochondrial ATP generation and oxygen consumption. Inhibition of mTOR by rapamycin blocked radiation-induced mTOR mitochondrial relocation and the shift of glycolysis to mitochondrial respiration, and reduced the clonogenic survival. In irradiated cells, mTOR formed a complex with Hexokinase II [HK II], a key mitochondrial protein in regulation of glycolysis, causing reduced HK II enzymatic activity. These results support a novel mechanism by which tumor cells can quickly adapt to genotoxic conditions via mTOR-mediated reprogramming of bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative phosphorylation. Such a "waking-up" pathway for mitochondrial bioenergetics demonstrates a flexible feature in the energy metabolism of cancer cells, and may be required for additional cellular energy consumption for damage repair and survival. Thus, the reversible cellular energy metabolisms should be considered in blocking tumor metabolism and may be targeted to sensitize them in anti-cancer therapy.
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Chung-Ling
authors: CL
authors: Lu
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Lili
authors: L
authors: Qin
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Hsin-Chen
authors: HC
authors: Liu
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Demet
authors: D
authors: Candas
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Ming
authors: M
authors: Fan
authors: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America.
authors: Jian Jian
authors: JJ
authors: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004734:Energy Metabolism / Q000528:radiation effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000528:radiation effects; D045325:HCT116 Cells; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D010085:Oxidative Phosphorylation / Q000528:radiation effects*; D010101:Oxygen Consumption / Q000528:radiation effects; D011827:Radiation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D006593:Hexokinase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005947:Glucose