The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.
The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.
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DOI：
10.1016/j.canlet.2014.04.001
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Cai, Qingsong
中科院分区：
文献类型：
--
作者：
Lu, Jianrong;Tan, Ming;Cai, Qingsong
与正常细胞相比，癌细胞强烈上调葡萄糖摄取和糖酵解，从而增加中间糖酵解代谢物和最终产物丙酮酸的产量。此外，在癌细胞中，糖酵解与线粒体三羧酸(TCA)循环和氧化磷酸化(OXPHOS)解偶联。因此，糖酵解衍生的丙酮酸大部分被转移到乳酸发酵中，并远离线粒体的氧化代谢。这种代谢表型被称为华宝效应。虽然糖酵解中间体为细胞增殖和肿瘤生长提供了必要的合成代谢支持，但Warburg代谢表型是否以及如何在肿瘤进展中发挥作用在很大程度上仍不清楚。我们在此综述氧化代谢受抑的原因和后果，特别是在肿瘤转移中。细胞在转移过程中改变或丢失其细胞外基质。不适当/不适当的基质附着会在正常细胞中产生活性氧物种(ROS)，并导致一种特定类型的细胞死亡，称为失巢凋亡。虽然失巢凋亡是转移的屏障，但癌细胞往往获得了更高的失巢凋亡阈值，从而增加了转移潜能。由于ROS是氧化代谢的固有副产物，强制刺激癌细胞中的葡萄糖氧化会增加氧化应激，恢复细胞对失巢凋亡的敏感性。因此，通过限制丙酮酸通量进入线粒体氧化代谢，Warburg效应使癌细胞能够避免线粒体呼吸产生过量的ROS，从而获得更高的失巢凋亡抵抗和转移的生存优势。与这一观点一致的是，促转移转录因子HIF和Snail抑制氧化代谢，而肿瘤抑制因子P53和转移抑制因子KISS1促进线粒体氧化。总而言之，这些发现揭示了线粒体氧化代谢是肿瘤转移的关键抑制因子，并证明了代谢疗法对肿瘤转移的潜在预防/干预作用。
Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells’ sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal mitochondrial oxidative metabolism as a critical suppressor of metastasis and justify metabolic therapies for potential prevention/intervention of tumor metastasis.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
16
作者：
Andersen, Joshua L.;Kornbluth, Sally
通讯作者：
Kornbluth, Sally
影响因子：
8
作者：
Cai, Q.;Lin, T.;Kamarajugadda, S.;Lu, J.
通讯作者：
Lu, J.
影响因子：
29
作者：
Berkers CR;Maddocks OD;Cheung EC;Mor I;Vousden KH
通讯作者：
Vousden KH
影响因子：
29
作者：
Chan SY;Zhang YY;Hemann C;Mahoney CE;Zweier JL;Loscalzo J
通讯作者：
Loscalzo J