经过数十年对癌症研究中分子遗传学的关注，代谢和环境因素的作用正在被重新评估。在这里，我们研究了微环境在促进肿瘤细胞恶性行为中的作用，其中氧化磷酸化（OXPHOS）与乳酸发酵/Warburg 效应的依赖不同。为此，我们评估了微环境挑战（缺氧、酸性和高葡萄糖）对线粒体编码的细胞色素 c 氧化酶 1 (COX I) 和两种核编码的异构体 4（COX IV-1 和 COX IV）表达的影响。 -2）。我们已经证明，具有“OXPHOS 表型”的肿瘤细胞通过上调 COX IV-1 来应对缺氧，而依赖乳酸发酵的细胞则最大化 COX IV-2 的表达。无论细胞的代谢状态如何，酸性都会上调 COX IV-2，而高葡萄糖会刺激 COX I 和 COX IV-1 的表达，对发酵细胞的作用更强。我们的结果揭示肿瘤细胞的“能量表型”驱动它们对微环境压力的适应性反应。

After decades of focus on molecular genetics in cancer research, the role of metabolic and environmental factors is being reassessed. Here, we investigated the role of microenvironment in the promotion of malignant behavior in tumor cells with a different reliance on oxidative phosphorylation (OXPHOS) versus lactic acid fermentation/Warburg effect. To this end, we evaluated the effects of microenvironmental challenges (hypoxia, acidity, and high glucose) on the expression of mitochondrial-encoded cytochrome c oxidase 1 (COX I) and two nuclear-encoded isoforms 4 (COX IV-1 and COX IV-2). We have shown that tumor cells with an "OXPHOS phenotype" respond to hypoxia by upregulating COX IV-1, whereas cells that rely on lactic acid fermentation maximized COX IV-2 expression. Acidity upregulates COX IV-2 regardless of the metabolic state of the cell, whereas high glucose stimulates the expression of COX I and COX IV-1, with a stronger effect in fermenting cells. Our results uncover that "energy phenotype" of tumor cells drives their adaptive response to microenvironment stress.