Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization.

Abstract

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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 17 Pg. 12647-54 (Apr 23 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20110356 (Publication Type: Journal Article)

Chemical References

• Neoplasm Proteins
• Oligomycins
• Uncoupling Agents
• Adenosine Triphosphate
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinase Kinases
• 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)