Oligomycin-induced Bioenergetic Adaptation in Cancer Cells with Heterogeneous Bioenergetic Organization
Oligomycin-induced Bioenergetic Adaptation in Cancer Cells with Heterogeneous Bioenergetic Organization
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DOI：
10.1074/jbc.m109.084194
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发表时间：
2010-04-23
影响因子：
4.8
通讯作者：
Xu, Jun
中科院分区：
文献类型：
--
作者：
Hao, Wenshan;Chang, Chao-Pei Betty;Xu, Jun
癌细胞不断适应缺氧或线粒体缺陷导致的氧化磷酸化（OXPHOS）抑制。在OXPHOS抑制下，AMP激活的蛋白激酶（AMPK）调节整体代谢调节，但其激活被发现是短暂的。细胞是否能维持细胞ATP稳态并在短暂的AMPK激活后存活尚不清楚。在这里，我们研究了一组癌细胞中OXPHOS抑制剂寡霉素的生物能量适应。我们发现，寡霉素在100 ng/ml完全抑制OXPHOS活性在1小时内，并诱导各种水平的糖酵解增益6小时，从中我们计算的癌细胞的生物能量组织。在糖酵解占优势的细胞中，寡霉素不会诱导太多的能量应激，如通过糖酵解加速、ATP失衡、AMPK活化、AMPK底物乙酰辅酶A羧化酶在Ser（79）处的磷酸化和细胞生长抑制所测量的。在OXPHOS依赖性LKB 1野生型细胞中，寡霉素在最初的1-2小时内诱导5-8%的ATP下降和瞬时AMPK活化。AMPK激活完成后，仍能检测到寡霉素诱导的乙酰辅酶A羧化酶Ser（79）磷酸化的增加，并且细胞ATP通过糖酵解的持续升高回到寡霉素处理前的水平。然而，细胞生长受到抑制，而细胞死亡和细胞周期分布没有增加。在OXPHOS依赖性LKB 1缺失细胞中，未检测到寡霉素激活AMPK，但细胞仍显示出类似的适应。我们还表明，适应寡霉素不调用缺氧诱导因子的激活。我们的数据表明，癌细胞可以生长和生存持续OXPHOS抑制通过一个尚未确定的监管机制。
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.