Lactic acid induces lactate transport and glycolysis/OXPHOS interconversion in glioblastoma

• Published in: Biochemical and biophysical research communications Vol. 503; no. 2; pp. 888 - 894
• Main Authors: Duan, Ke, Liu, Zhong-jian, Hu, Su-qiong, Huo, Hong-yu, Xu, Zhi-ru, Ruan, Jian-fei, Sun, Yang, Dai, Li-ping, Yan, Chang-bao, Xiong, Wei, Cui, Qing-hua, Yu, Hai-jing, Yu, Min, Qin, Yang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2018
• Subjects: 60 APPLIED LIFE SCIENCES; Adenosine Triphosphate - metabolism; ATP; Biological Transport - drug effects; Blotting, Western; Cell Line, Tumor; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; GLIOMAS; GLUCOSE; Glucose deprivation; GLYCOLYSIS; Glycolysis - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lactate transport; Lactates - metabolism; LACTIC ACID; Lactic Acid - pharmacology; Lactic acidosis; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - metabolism; Oxidative Phosphorylation - drug effects; OXPHOS; Proto-Oncogene Proteins c-myc - metabolism; Symporters - metabolism; TUMOR CELLS; U251 cells; Lactate transport; OXPHOS; Glucose deprivation; Lactic acidosis; Glioblastoma; U251 cells
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.06.092

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. •Lactic acidosis induces lactate transportation and reuse.•Under glucose-deprived condition, lactic acidosis could keep cell growth and maintain ATP content to resist cell death through glycolysis/ OXPHOS inter-conversion in U251 cell.•Different region of tumor tissue has diverse glucose metabolic way to adapt adverse microenvironment and maintain proliferation and progression in GMB.