| 20110356 |
Hao W, Chang CP, Tsao CC, Xu J: Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization. J Biol Chem. 2010 Jan 28.
Cancer cells constantly adapt to oxidative phosphorylation (OXPHOS) suppression resulting from hypoxia or mitochondria defects. Under the OXPHOS suppression, 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 induces much energy stress as measured by glycolysis acceleration, ATP imbalance, AMPK activation, AMPK substrate acetyl-CoA carboxylase phosphorylation at Ser79 (P-ACC), 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 P-ACC is still detected and cellular ATP is back at pre-oligomycin treatment levels by sustained elevation of glycolysis. Cell growth, however, is inhibited without 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 HIF. Our data suggest that cancer cells may grow and survive persistent OXPHOS suppression through yet an unidentified regulatory mechanism. |
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