Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
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DOI：
10.1073/pnas.1003428107
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发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
--
作者：
Weinberg, Frank;Hamanaka, Robert;Chandel, Navdeep S.
Otto Warburg关于癌症起源的理论假设肿瘤细胞在线粒体氧化磷酸化方面存在缺陷，因此依赖于高水平的有氧糖酵解作为ATP的主要来源来促进细胞增殖（Warburg效应）。这与正常细胞相反，正常细胞主要利用氧化磷酸化来生长和存活。在这里，我们报道了kras诱导的不依赖锚定生长（转化细胞的标志）的葡萄糖代谢的主要功能是支持戊糖磷酸途径。糖酵解ATP的主要功能是在缺氧条件下支持生长。谷氨酰胺通过谷氨酰胺酶和丙氨酸转氨酶转化为三羧酸循环中间体α -酮戊二酸盐是kras诱导的非锚定生长所必需的。通过调节ERK MAPK信号通路，线粒体代谢允许活性氧（ROS）的产生，这是kras诱导的非锚定生长所必需的。我们发现，非锚定生长所需的ROS生成的主要来源是线粒体复合体III的Q(o)位点。此外，在致癌kras驱动的肺癌小鼠模型中，线粒体转录因子A （TFAM）基因缺失导致的线粒体功能破坏减少了肿瘤的发生。这些结果表明，线粒体代谢和线粒体ROS的产生对kras诱导的细胞增殖和肿瘤发生至关重要。
Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conditions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Q(o) site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by loss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis.