TGF­ß1­induced epithelial­mesenchymal transition increases fatty acid oxidation and OXPHOS activity via the p­AMPK pathway in breast cancer cells.

Breast cancer is the most common malignancy in women, and metastasis is the leading cause of death in breast cancer patients. Previous studies have shown that epithelial­mesenchymal transition (EMT) is involved in the metastasis of breast cancer, but the metabolic reprogramming and regulation mechanisms involved in the EMT process are still unclear. In the present study, we successfully constructed an EMT cell model induced by transforming growth factor ß1 (TGF­ß1) treatment of MCF­7 cells at different times. The results showed that cell adhesion decreased, cell invasion increased and ATP levels increased in EMT MCF­7 cells treated with TGF­ß1. Furthermore, the expression of fatty acid synthase (FASN) was decreased, and the expression of key fatty acid ß­oxidation enzymes (CPT1 and CD36) was elevated in treated cells compared to control cells. These results showed that the fatty acid oxidation pathway was enhanced. In addition, the expression of NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8), mitochondrial transcription factor A (TFAM) and cytochrome c oxidase subunit I (COXI) increased, and the mitochondrial DNA copy number and ROS levels were also significantly increased during TGF­ß1­induced EMT. These results indicated that mitochondrial oxidative phosphorylation (OXPHOS) activity was enhanced during EMT. In addition, we observed that the expression of p­AMPK was increased and ACC (Acetyl­CoA Carboxylase) was decreased during TGF­ß1­induced EMT in MCF­7 cells. Immunohistochemical analysis of clinical samples revealed high expression of FASN in epithelial cells that had high expression of E­cadherin, while high expression of CPT­1 was observed in mesenchymal cells that had high expression of vimentin. Results of the current study showed a metabolic transition in TGF­ß1­induced EMT in MCF­7 cells. This transition may regulate fatty acid oxidation and OXPHOS activity in EMT MCF­7 cells through the p­AMPK pathway. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGF­ß1­induced EMT and metastasis in breast cancer. This study thus provides a new strategy for identifying new therapeutic targets for breast cancer.

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

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.