Glucose-dependent anaplerosis in cancer cells is required for cellular redox balance in the absence of glutamine.
Cancer cells have altered metabolism compared to normal cells, including dependence on glutamine (GLN) for survival, known as GLN addiction. However, some cancer cell lines do not require GLN for survival and the basis for this discrepancy is not well understood. GLN is a precursor for antioxidants such as glutathione (GSH) and NADPH, and GLN deprivation is therefore predicted to deplete antioxidants and increase reactive oxygen species (ROS). Using diverse human cancer cell lines we show that this occurs only in cells that rely on GLN for survival. Thus, the preference for GLN as a dominant antioxidant source defines GLN addiction. We show that despite increased glucose uptake, GLN addicted cells do not metabolize glucose via the TCA cycle when GLN is depleted, as revealed by (13)C-glucose labeling. In contrast, GLN independent cells can compensate by diverting glucose-derived pyruvate into the TCA cycle. GLN addicted cells exhibit reduced PDH activity, increased PDK1 expression, and PDK inhibition partially rescues GLN starvation-induced ROS and cell death. Finally, we show that combining GLN starvation with pro-oxidants selectively kills GLN addicted cells. These data highlight a major role for GLN in maintaining redox balance in cancer cells that lack glucose-dependent anaplerosis.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3 Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
Naniye Mallı
NM
Cetinbas
Children's Medical Center Research Institute, University of Texas-Southern Medical Center, Dallas, TX 75390-9063, USA.
Jessica
J
Sudderth
Children's Medical Center Research Institute, University of Texas-Southern Medical Center, Dallas, TX 75390-9063, USA.
Robert C
RC
Harris
The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.|Abdullah Gul University, Faculty of Engineering, 38170, Kayseri, Turkey.
Aysun
A
Cebeci
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3 Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
Gian L
GL
Negri
The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.|Department of Biology, MIT, Cambridge, MA 02139, USA.|Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Ömer H
ÖH
Yılmaz
Children's Medical Center Research Institute, University of Texas-Southern Medical Center, Dallas, TX 75390-9063, USA.
Ralph J
RJ
DeBerardinis
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3 Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
Poul H
PH
Sorensen
D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D002952:Citric Acid Cycle / Q000235:genetics; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D005973:Glutamine; D019289:Pyruvic Acid; D005978:Glutathione; D005947:Glucose