Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Immunology, Institute of Basic Medical Sciences & State Key Laboratory of Medical Molecular Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
Oncogene. 2019 Oct;38(44):6970-6984. doi: 10.1038/s41388-019-0932-1. Epub 2019 Aug 13.
Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.
抗血管生成药物的临床应用通过产生的缺氧深刻地影响肿瘤细胞行为。迄今为止，缺氧如何调节肿瘤细胞仍不清楚。在这里，我们表明缺氧促进体外和体内重新填充肿瘤的人乳腺癌肿瘤发生细胞[肿瘤再填充细胞 (TRC)]的生长。这种刺激作用归因于缺氧诱导的活性氧 (ROS)，其激活 Akt 和 NF-κB，依赖于减弱的三羧酸 (TCA) 循环。我们发现富马酸在缺氧 TRC 的 TCA 循环中积累，导致谷胱甘肽琥珀酰化，NADPH/NADP 减少，ROS 水平增加。在机制上，缺氧增加的 HIF-1α 转录地下调节线粒体磷酸烯醇丙酮酸羧激酶 (PCK2) 的表达，导致 TCA 循环减弱和富马酸积累。这些发现表明，缺氧重编程的 TCA 循环通过 HIF-1α 下调的 PCK2 途径促进人乳腺癌 TRC 的生长，这意味着需要将抗血管生成治疗与抗氧化调节剂联合使用。
