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首页> 外文期刊>Oncogene >Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration
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Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration

机译：致癌性K-ras表达与cAMP / PKA通路的紊乱以及线粒体动力学和呼吸作用的福司柯林可逆改变有关

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The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by forskolin treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs.
机译：已经提出了在癌细胞中的Warburg效应涉及多种机制，包括适应低氧，癌基因激活或抑癌药的丧失以及线粒体功能受损。在以前的论文中，已经显示，与正常细胞相比，K-ras转化的小鼠细胞对葡萄糖戒断（发生凋亡）的敏感性高得多，并且具有很高的糖酵解速率和线粒体复合物I的强烈还原。观察结果表明，转化的细胞在环状单磷酸腺苷/ cAMP依赖性蛋白激酶（cAMP / PKA）途径中发生排列紊乱，已知该途径可调节多种线粒体功能。在本文中，研究了cAMP / PKA通路的失序及其对线粒体功能转化相关变化的影响。通过福司高林处理实现的外源性PKA活性刺激，保护了K-ras转化细胞免受葡萄糖剥夺，增强的复合物I活性，细胞内三磷酸腺苷（ATP）水平，线粒体融合以及细胞内活性氧（ROS）水平降低引起的凋亡。 。通过抑制PKA活性，几乎完全防止了其中几种作用。用有利于线粒体融合的化合物进行短时处理会强烈降低细胞ROS水平，尤其是在转化细胞中。这些发现支持以下观念：葡萄糖不足诱导的细胞凋亡（特定于K-ras转化的细胞）与PKA信号的紊乱有关，导致PKA信号线粒体I减少，ATP形成减少，线粒体裂变在融合中的普遍存在以及从而为开发抗癌药物开辟了新途径。

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