PMID- 26148236
OWN - NLM
STAT- MEDLINE
DCOM- 20160808
LR  - 20191218
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 12
DP  - 2016 Mar 24
TI  - Disruption of cytochrome c oxidase function induces the Warburg effect and 
      metabolic reprogramming.
PG  - 1585-95
LID - 10.1038/onc.2015.227 [doi]
AB  - Defects in mitochondrial oxidative phosphorylation complexes, altered 
      bioenergetics and metabolic shift are often seen in cancers. Here we show a role 
      for the dysfunction of the electron transport chain component cytochrome c 
      oxidase (CcO) in cancer progression. We show that genetic silencing of the CcO 
      complex by shRNA expression and loss of CcO activity in multiple cell types from 
      the mouse and human sources resulted in metabolic shift to glycolysis, loss of 
      anchorage-dependent growth and acquired invasive phenotypes. Disruption of the 
      CcO complex caused loss of transmembrane potential and induction of 
      Ca2+/Calcineurin-mediated retrograde signaling. Propagation of this signaling 
      includes activation of PI3-kinase, IGF1R and Akt, Ca2(+)-sensitive transcription 
      factors and also TGFbeta1, MMP16 and periostin, which are involved in oncogenic 
      progression. Whole-genome expression analysis showed the upregulation of genes 
      involved in cell signaling, extracellular matrix interactions, cell 
      morphogenesis, cell motility and migration. The transcription profiles reveal 
      extensive similarity to retrograde signaling initiated by partial mitochondrial 
      DNA depletion, although distinct differences are observed in signaling induced by 
      CcO dysfunction. The possible CcO dysfunction as a biomarker for cancer 
      progression was supported by data showing that esophageal tumors from human 
      patients show reduced CcO subunits IVi1 and Vb in regions that were previously 
      shown to be the hypoxic core of the tumors. Our results show that mitochondrial 
      electron transport chain defect initiates a retrograde signaling. These results 
      suggest that a defect in the CcO complex can potentially induce tumor 
      progression.
FAU - Srinivasan, S
AU  - Srinivasan S
AD  - Department of Biomedical Sciences, The Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, Philadelphia, PA, USA.
FAU - Guha, M
AU  - Guha M
AD  - Department of Biomedical Sciences, The Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, Philadelphia, PA, USA.
FAU - Dong, D W
AU  - Dong DW
AD  - Department of Biomedical Sciences, The Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, Philadelphia, PA, USA.
FAU - Whelan, K A
AU  - Whelan KA
AD  - Division of Gastroenterology, Department of Medicine, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Ruthel, G
AU  - Ruthel G
AD  - Department of Biomedical Sciences, The Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, Philadelphia, PA, USA.
FAU - Uchikado, Y
AU  - Uchikado Y
AD  - Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of 
      Medicine, Kagoshima University, Kagoshima, Japan.
FAU - Natsugoe, S
AU  - Natsugoe S
AD  - Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of 
      Medicine, Kagoshima University, Kagoshima, Japan.
FAU - Nakagawa, H
AU  - Nakagawa H
AD  - Division of Gastroenterology, Department of Medicine, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Avadhani, N G
AU  - Avadhani NG
AD  - Department of Biomedical Sciences, The Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, Philadelphia, PA, USA.
LA  - eng
GR  - R01 GM034883/GM/NIGMS NIH HHS/United States
GR  - R01 AR067066/AR/NIAMS NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - R01 CA022762/CA/NCI NIH HHS/United States
GR  - R37 CA022762/CA/NCI NIH HHS/United States
GR  - GM-34883/GM/NIGMS NIH HHS/United States
GR  - CA-22762/CA/NCI NIH HHS/United States
GR  - P30DK050306/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150706
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Electron Transport Complex IV/genetics/*metabolism
MH  - Gene Silencing
MH  - Mice
MH  - Oxidative Stress
MH  - Signal Transduction
PMC - PMC4703574
MID - NIHMS690175
COIS- Conflict of Interest: The authors declare no conflict of interest.
EDAT- 2015/07/07 06:00
MHDA- 2016/08/09 06:00
PMCR- 2016/05/18
CRDT- 2015/07/07 06:00
PHST- 2014/12/23 00:00 [received]
PHST- 2015/04/30 00:00 [revised]
PHST- 2015/05/10 00:00 [accepted]
PHST- 2015/07/07 06:00 [entrez]
PHST- 2015/07/07 06:00 [pubmed]
PHST- 2016/08/09 06:00 [medline]
PHST- 2016/05/18 00:00 [pmc-release]
AID - onc2015227 [pii]
AID - 10.1038/onc.2015.227 [doi]
PST - ppublish
SO  - Oncogene. 2016 Mar 24;35(12):1585-95. doi: 10.1038/onc.2015.227. Epub 2015 Jul 6.