School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China; Key Laboratory for Biochemistry and Molecular Biology of High Education in Yunnan Province, Kunming, Yunnan, 650091, China.
Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):888-894. doi: 10.1016/j.bbrc.2018.06.092. Epub 2018 Jun 21.
The Warburg effect is a dominant phenotype of most tumor cells. Recent reports have shown that the Warburg effect can be reprogrammed by the tumor microenvironment. Lactic acidosis and glucose deprivation are the common adverse microenvironments in solid tumor. The metabolic reprogramming induced by lactic acid and glucose deprivation remains to be elucidated in glioblastoma. Here, we show that, under glucose deprivation, lactic acid can preserve high ATP levels and resist cell death in U251 cells. At the same time, we find that MCT1 and MCT4 are significantly highly expressed. The metabolic regulation factor HIF-1α decreased and C-MYC increased. Nuclear respiratory factor 1 (NRF1) and oxidative phosphorylation (OXPHOS)-related proteins (NDUFB8, ND1) are all distinctly increased. Therefore, lactic acid can induce lactate transport and convert the dominant Warburg effect to OXPHOS. Through bioinformatics analysis, the high expression of HIF-1α, MCT1 or MCT4 indicate a poor prognosis in glioblastoma. In addition, in glioblastoma tissue, HIF-1α, MCT4 and LDH are highly expressed in the interior region, and their expression is decreased in the lateral region. MCT1 can not be detected in the interior region and is highly expressed in the lateral region. Hence, different regions of glioblastoma have diverse energy metabolic pathways. Glycolysis occurs mainly in the interior region and OXPHOS in the lateral region. In general, lactic acid can induce regional energy metabolic reprogramming and assist tumor cells to adapt and resist adverse microenvironments. This study provides new ideas for furthering understanding of the metabolic features of glioblastoma. It may promote the development of new therapeutic strategies in GBM.
瓦博格效应是大多数肿瘤细胞的主要表型。最近的报告表明，肿瘤微环境可以重新编程瓦博格效应。乳酸酸中毒和葡萄糖剥夺是实体瘤中常见的不利微环境。乳酸和葡萄糖剥夺诱导的代谢重编程在神经胶质瘤中仍有待阐明。在这里，我们表明，在葡萄糖剥夺下，乳酸可以在 U251 细胞中保持高 ATP 水平并抵抗细胞死亡。同时，我们发现 MCT1 和 MCT4 表达显著升高。代谢调节因子 HIF-1α 降低，C-MYC 增加。核呼吸因子 1（NRF1）和氧化磷酸化（OXPHOS）相关蛋白（NDUFB8、ND1）均明显增加。因此，乳酸可以诱导乳酸转运并将主导的瓦博格效应转化为 OXPHOS。通过生物信息学分析，HIF-1α、MCT1 或 MCT4 的高表达表明神经胶质瘤预后不良。此外，在神经胶质瘤组织中，HIF-1α、MCT4 和 LDH 在内部区域高表达，而在外侧区域表达降低。MCT1 在内侧区域不能检测到，在外侧区域高表达。因此，神经胶质瘤的不同区域具有不同的能量代谢途径。糖酵解主要发生在内部区域，OXPHOS 发生在外侧区域。总的来说，乳酸可以诱导区域能量代谢重编程，帮助肿瘤细胞适应和抵抗不利的微环境。本研究为进一步了解神经胶质瘤的代谢特征提供了新思路，可能促进新的治疗策略在 GBM 中的发展。
