Abstract
Bcl-2 has been shown to promote survival of cancer cells by maintaining a slight pro-oxidant state through elevated mitochondrial respiration during basal conditions. On oxidative stress, Bcl-2 moderates mitochondrial respiration through cytochrome c oxidase (COX) activity to prevent an excessive buildup of reactive oxygen species (ROS) by-production from electron transport activities. However, the underlying molecular mechanism(s) of Bcl-2-mediated ROS regulation and its impact on carcinogenesis remain unclear. In this study, we show that Bcl-2 expression positively influences the targeting of nuclear-encoded COX Va and Vb to the mitochondria of cancer cells. In addition, evidence is presented in support of a protein–protein interaction between COX Va and Bcl-2, involving the BH2 domain of Bcl-2. Interestingly, episodes of serum withdrawal, glucose deprivation or hypoxia aimed at inducing early oxidative stress triggered Bcl-2-overexpressing cells to preserve mitochondrial levels of COX Va while depressing COX Vb, whereas the reverse was observed in mock-transfected cells. The unique manner in which Bcl-2 adjusted COX subunits during these physiological stress triggers had a profound impact on the resultant decrease in COX activity and maintenance of mitochondrial ROS levels, thus delineating a novel mechanism for the homeostatic role of Bcl-2 in the redox biology and metabolism of cancer cells.
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Abbreviations
- ATP:
-
adenosine triphosphate
- Bak:
-
Bcl-2 antagonist/killer-1
- Bax:
-
Bcl-2 associated X protein
- Bcl-2:
-
B-cell lymphoma/leukemia-2
- BN-PAGE:
-
blue native polyacrylamide gel electrophoresis
- COX:
-
cytochrome c oxidase
- CuZn SOD:
-
copper/zinc superoxide dismutase
- HIF-1:
-
hypoxia-inducible factor 1
- O2-:
-
superoxide
- RLU:
-
relative light unit
- ROS:
-
reactive oxygen species
- Tom20:
-
translocase of outer membrane 20
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Acknowledgements
This work is supported by grants from the Biomedical Research Council of Singapore (R-185–000–164–305), and the NUS Academic Research Fund, Singapore (R-185–000–136–112) to SP. The NPC cell lines were gifts from Lo Kwok-wai (The Chinese University of Hong Kong) and Hsieh Wen-son (John Hopkins Medical Institute, USA). We thank Thomas Loh (National University Hospital, Singapore) and Jayshree Hirpara (National University of Singapore) for providing the lymphoma samples and for excellent technical assistance with the samples, respectively. ZXC designed, performed the experiments and wrote the paper. SP designed the experiments and wrote the paper. Both authors discussed the results and commented on the paper.
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Chen, Z., Pervaiz, S. Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Differ 17, 408–420 (2010). https://doi.org/10.1038/cdd.2009.132
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DOI: https://doi.org/10.1038/cdd.2009.132
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