Characterization of a novel metabolic strategy used by drug-resistant tumor cells.
Acquired or inherent drug resistance is the major problem in achieving successful cancer treatment. However, the mechanism(s) of pleiotropic drug resistance remains obscure. We have identified and characterized a cellular metabolic strategy that differentiates drug-resistant cells from drug-sensitive cells. This strategy may serve to protect drug-resistant cells from damage caused by chemotherapeutic agents and radiation. We show that drug-resistant cells have low mitochondrial membrane potential, use nonglucose carbon sources (fatty acids) for mitochondrial oxygen consumption when glucose becomes limited, and are protected from exogenous stress such as radiation. In addition, drug-resistant cells express high levels of mitochondrial uncoupling protein 2 (UCP2). The discovery of this metabolic strategy potentially facilitates the design of novel therapeutic approaches to drug resistance.
Harper
Mary-Ellen
ME
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Antoniou
Andreas
A
Villalobos-Menuey
Elizabeth
E
Russo
Alicia
A
Trauger
Richard
R
Vendemelio
Minda
M
George
Amanda
A
Bartholomew
Richard
R
Carlo
Dennis
D
Shaikh
Azhar
A
Kupperman
Jami
J
Newell
Evan W
EW
Bespalov
Ivan A
IA
Wallace
Susan S
SS
Liu
Ye
Y
Rogers
Jeffrey R
JR
Gibbs
Gregory L
GL
Leahy
Jack L
JL
Camley
Robert E
RE
Melamede
Robert
R
Newell
M Karen
MK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002945:Cisplatin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D003576:Electron Transport Complex IV / Q000378:metabolism; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008727:Methotrexate / Q000494:pharmacology; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000502:physiology; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D019301:Oleic Acid; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D005947:Glucose; D002945:Cisplatin; D008727:Methotrexate