PMID- 22777349
OWN - NLM
STAT- MEDLINE
DCOM- 20130715
LR  - 20211021
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 32
IP  - 20
DP  - 2013 May 16
TI  - PGC-1beta mediates adaptive chemoresistance associated with mitochondrial DNA 
      mutations.
PG  - 2592-600
LID - 10.1038/onc.2012.259 [doi]
AB  - 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-1alpha (PGC-1alpha) and PGC-1beta, both 
      of which were significantly upregulated in the CDDP-resistant cells. Importantly, 
      both transient and stable silencing of PGC-1beta re-established the sensitivity of 
      these cells to CDDP-induced apoptosis. Remarkably, the PGC-1beta-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.
FAU - Yao, Z
AU  - Yao Z
AD  - Department of Cell and Developmental Biology, Consortium for Mitochondrial 
      Research, University College London, London, UK.
FAU - Jones, A W E
AU  - Jones AW
FAU - Fassone, E
AU  - Fassone E
FAU - Sweeney, M G
AU  - Sweeney MG
FAU - Lebiedzinska, M
AU  - Lebiedzinska M
FAU - Suski, J M
AU  - Suski JM
FAU - Wieckowski, M R
AU  - Wieckowski MR
FAU - Tajeddine, N
AU  - Tajeddine N
FAU - Hargreaves, I P
AU  - Hargreaves IP
FAU - Yasukawa, T
AU  - Yasukawa T
FAU - Tufo, G
AU  - Tufo G
FAU - Brenner, C
AU  - Brenner C
FAU - Kroemer, G
AU  - Kroemer G
FAU - Rahman, S
AU  - Rahman S
FAU - Szabadkai, G
AU  - Szabadkai G
LA  - eng
GR  - G-0905/PUK_/Parkinson's UK/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120709
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (PPARGC1B protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 1.6.99.3 (NADH Dehydrogenase)
RN  - EC 1.6.99.3 (NADH dehydrogenase subunit 2, human)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Adaptation, Physiological
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cisplatin/pharmacology
MH  - *DNA, Mitochondrial
MH  - Drug Resistance, Neoplasm/drug effects/*genetics
MH  - Heat-Shock Proteins/genetics/metabolism
MH  - Humans
MH  - Lung Neoplasms/drug therapy/genetics/metabolism
MH  - *Mutation
MH  - NADH Dehydrogenase/genetics
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - RNA-Binding Proteins
MH  - Transcription Factors/genetics/metabolism
EDAT- 2012/07/11 06:00
MHDA- 2013/07/17 06:00
CRDT- 2012/07/11 06:00
PHST- 2012/07/11 06:00 [entrez]
PHST- 2012/07/11 06:00 [pubmed]
PHST- 2013/07/17 06:00 [medline]
AID - onc2012259 [pii]
AID - 10.1038/onc.2012.259 [doi]
PST - ppublish
SO  - Oncogene. 2013 May 16;32(20):2592-600. doi: 10.1038/onc.2012.259. Epub 2012 Jul 
      9.