Jia Dongya, Park Jun Hyoung, Jung Kwang Hwa, Levine Herbert, Kaipparettu Benny Abraham
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.
Systems, Synthetic and Physical Biology Program, Rice University, Houston, TX 77005, USA.
Cells. 2018 Mar 13;7(3):21. doi: 10.3390/cells7030021.
Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective.
有氧糖酵解，也被称为瓦伯格效应，长期以来一直被视为癌细胞的主要代谢表型。最近有研究表明，大多数肿瘤中的线粒体在进行氧化磷酸化（OXPHOS）的能力方面并无缺陷。相反，在高侵袭性癌细胞中，线粒体能量途径会被重新编程，以应对高能量需求的挑战，更好地利用可用燃料以及进行大分子合成，从而实现快速的细胞分裂和迁移。线粒体能量重编程还通过线粒体到细胞核的逆行信号传导以及癌蛋白的翻译后修饰参与致癌途径的调控。此外，肿瘤线粒体可与肿瘤微环境发生相互作用。例如，来自癌症相关成纤维细胞的信号可促使肿瘤线粒体利用氧化磷酸化，这一过程被称为反向瓦伯格效应。新出现的证据表明，癌细胞可获得一种糖酵解/氧化磷酸化混合表型，其中糖酵解和氧化磷酸化均可用于能量产生和生物量合成。糖酵解/氧化磷酸化混合表型促进了癌细胞的代谢可塑性，可能与转移和治疗抗性特别相关。此外，癌细胞可根据外部刺激改变其代谢表型以更好地存活。考虑到癌细胞的代谢异质性和可塑性，原则上针对癌症代谢依赖性的治疗可以更有效。
