Document Detail


Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization.
MedLine Citation:
PMID:  20110356     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cancer cells constantly adapt to oxidative phosphorylation (OXPHOS) suppression resulting from hypoxia or mitochondria defects. Under the OXPHOS suppression, AMP-activated protein kinase (AMPK) regulates global metabolism adjustments, but its activation has been found to be transient. Whether cells can maintain cellular ATP homeostasis and survive beyond the transient AMPK activation is not known. Here, we study the bioenergetic adaptation to the OXPHOS inhibitor oligomycin in a group of cancer cells. We found that oligomycin at 100 ng/ml completely inhibits OXPHOS activity in 1 h and induces various levels of glycolysis gains by 6 h, from which we calculate the bioenergetic organizations of cancer cells. In glycolysis-dominant cells, oligomycin does not induce much energy stress as measured by glycolysis acceleration, ATP imbalance, AMPK activation, AMPK substrate acetyl-CoA carboxylase phosphorylation at Ser(79), and cell growth inhibition. In OXPHOS-dependent LKB1 wild type cells, oligomycin induces 5-8% ATP drops and transient AMPK activation during the initial 1-2 h. After AMPK activation is completed, oligomycin-induced increase of acetyl-CoA carboxylase phosphorylation at Ser(79) is still detected, and cellular ATP is back at preoligomycin treatment levels by sustained elevation of glycolysis. Cell growth, however, is inhibited without an increase in cell death and alteration in cell cycle distribution. In OXPHOS-dependent LKB1-null cells, no AMPK activation by oligomycin is detected, yet cells still show a similar adaptation. We also demonstrate that the adaptation to oligomycin does not invoke activation of hypoxia-induced factor. Our data suggest that cancer cells may grow and survive persistent OXPHOS suppression through an as yet unidentified regulatory mechanism.
Authors:
Wenshan Hao; Chao-Pei Betty Chang; Cheng-Chung Tsao; Jun Xu
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Publication Detail:
Type:  Journal Article     Date:  2010-01-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-19     Completed Date:  2010-05-20     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12647-54     Citation Subset:  IM    
Affiliation:
Department of Oncology, Wyeth Research, Pearl River, New York 10965, USA. ytwhao@yahoo.com
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / metabolism
Acetyl-CoA Carboxylase / genetics,  metabolism
Adenosine Triphosphate / metabolism
Cell Hypoxia / drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Glycolysis / drug effects*
Humans
Mitochondria / metabolism*,  pathology
Neoplasm Proteins / metabolism
Neoplasms / metabolism*,  pathology
Oligomycins / pharmacology*
Oxidative Phosphorylation / drug effects*
Phosphorylation / drug effects
Protein-Serine-Threonine Kinases / genetics,  metabolism
Stress, Physiological / drug effects
Time Factors
Uncoupling Agents / pharmacology*
Chemical
Reg. No./Substance:
0/Neoplasm Proteins; 0/Oligomycins; 0/Uncoupling Agents; 56-65-5/Adenosine Triphosphate; EC 2.7.1.-/STK11 protein, human; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 6.4.1.2/Acetyl-CoA Carboxylase
Comments/Corrections

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