Abstract
Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.
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Abbreviations
- ATM:
-
ataxia telangiectasia mutated
- ATR:
-
ataxia telangiectasia and Rad3 related
- BPDE:
-
benzo[a]pyrene diol epoxide
- CHK:
-
checkpoint kinase
- COX:
-
cytochrome c oxidase
- cyt c:
-
cytochrome c
- 2-DG:
-
2-deoxy-D-glucose
- GAPDH:
-
glyceraldehyde phosphate dehydrogenase
- H2AX:
-
H2A histone family, member X
- LDH:
-
lactate dehydrogenase
- MDM2:
-
mouse double minute 2 homolog
- MnSOD:
-
manganese superoxide dismutase
- NAC:
-
N-acetyl cysteine
- NAD+:
-
nicotinamide adenine dinucleotide
- NF-κB:
-
nuclear factor-kappa B
- PGC-1α:
-
peroxisome proliferator-activated receptor-gamma coactivator 1α
- PARP:
-
poly (ADP-ribose) polymerase
- PI3K:
-
phosphatidylinositide 3-kinase
- OXPHOS:
-
oxidative phosphorylation
- RIP1:
-
receptor-interacting protein 1
- ROS:
-
reactive oxygen species
- TNFα:
-
tumor necrosis factor α
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Acknowledgements
We thank Dr. Akiyoshi Fukamizu (University of Tsukuba, Japan) for providing the human PGC-1 promoter luciferase construct and Dr. Bruce M. Spiegelman (Harvard Medical School) for the deposit of PGC-1 expressing plasmid to Addgene. We are grateful to Tamara Howard, MS, Department of Cell Biology and Physiology, University of New Mexico, for help in experiments. This work was partially supported by NIH grants R01ES017328 (Y.L.) and R03CA167727 (W.C.), and a grant (DE-FG02-09ER64783) from Low Dose Radiation Program, U.S. Department of Energy (Y.L).
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Chen, W., Wang, Q., Bai, L. et al. RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis. Cell Death Differ 21, 1061–1070 (2014). https://doi.org/10.1038/cdd.2014.25
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DOI: https://doi.org/10.1038/cdd.2014.25
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