Lu Jianrong, Tan Ming, Cai Qingsong
Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, United States.
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, United States.
Cancer Lett. 2015 Jan 28;356(2 Pt A):156-64. doi: 10.1016/j.canlet.2014.04.001. Epub 2014 Apr 13.
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 the context of 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.
与正常细胞相比，癌细胞强烈上调葡萄糖摄取和糖酵解，以增加糖酵解中间代谢产物和终产物丙酮酸的产量。此外，癌细胞中的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，大部分糖酵解衍生的丙酮酸被转移到乳酸发酵，远离线粒体氧化代谢。这种代谢表型被称为瓦伯格效应。虽然糖酵解中间产物为细胞增殖和肿瘤生长提供重要的合成代谢支持已被广泛接受，但瓦伯格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。我们在此回顾了氧化代谢受限的原因和后果，特别是在肿瘤转移的背景下。在转移过程中，细胞会改变或失去其细胞外基质。正常细胞中，不适当的基质附着会产生活性氧（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一个障碍，但癌细胞通常获得了更高的失巢凋亡阈值，因此具有更高的转移潜能。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并恢复细胞对失巢凋亡的敏感性。因此，通过限制丙酮酸进入线粒体氧化代谢的通量，瓦伯格效应使癌细胞能够避免线粒体呼吸产生过多的ROS，从而获得更高的失巢凋亡抗性和转移生存优势。与此观点一致的是，促转移转录因子HIF和Snail会减弱氧化代谢，而肿瘤抑制因子p53和转移抑制因子KISS1则促进线粒体氧化。总的来说，这些发现揭示了线粒体氧化代谢是转移的关键抑制因子，并为潜在预防/干预肿瘤转移的代谢疗法提供了依据。
