Journal
ONCOGENE
Volume 32, Issue 20, Pages 2592-2600Publisher
SPRINGERNATURE
DOI: 10.1038/onc.2012.259
Keywords
CDDP; chemoresistance; mitochondrial biogenesis; PGC-1; Complex-I; mitochondrial DNA
Funding
- Parkinson's UK [G-0905]
- Medical Research Council (MRC-DTA)
- Polish Ministry of Science and Higher Education [NN407075137]
- National Science Centre [DEC-2011/01/M/NZ3/02128]
- Foundation for Polish Science
- EU
- European Regional Development Fund
- Operational Programme Innovative economy
- L'Oreal fellowship
- Great Ormond Street Hospital Children's Charity
- European Union (ApoSys)
- European Union (ArtForce)
- European Union (ChemoRes)
- Ligue contre le Cancer (Laboratoire labellise)
- Great Ormond Street Hospital Childrens Charity [V1220] Funding Source: researchfish
- Parkinson's UK [G-0905] Funding Source: researchfish
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Primary mitochondrial dysfunction commonly leads to failure in cellular adaptation to stress. Paradoxically, however, nonsynonymous mutations of mitochondrial DNA (mtDNA) are frequently found in cancer cells and may have a causal role in the development of resistance to genotoxic stress induced by common chemotherapeutic agents, such as cis-diammine-dichloroplatinum(II) (cisplatin, CDDP). Little is known about how these mutations arise and the associated mechanisms leading to chemoresistance. Here, we show that the development of adaptive chemoresistance in the A549 non-small-cell lung cancer cell line to CDDP is associated with the hetero- to homoplasmic shift of a nonsynonymous mutation in MT-ND2, encoding the mitochondrial Complex-I subunit ND2. The mutation resulted in a 50% reduction of the NADH: ubiquinone oxidoreductase activity of the complex, which was compensated by increased biogenesis of respiratory chain complexes. The compensatory mitochondrial biogenesis was most likely mediated by the nuclear co-activators peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) and PGC-1 beta, both of which were significantly upregulated in the CDDP-resistant cells. Importantly, both transient and stable silencing of PGC-1 beta re-established the sensitivity of these cells to CDDP-induced apoptosis. Remarkably, the PGC-1 beta-mediated CDDP resistance was independent of the mitochondrial effects of the co-activator. Altogether, our results suggest that partial respiratory chain defects because of mtDNA mutations can lead to compensatory upregulation of nuclear transcriptional co-regulators, in turn mediating resistance to genotoxic stress.
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