Low folate induced lung cancer stemness and reprograms lactate-energy metabolism via activated mTOR-HIF1α signaling pathway to promote lung cancer metastasis

• Main Authors: CHEN, WAN-JING, 陳婉菁
• Other Authors: Huang Syu, Rwei-Fen
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/7k9383

博士 === 輔仁大學 === 食品營養博士學位學程 === 107 === Low folate (LF) microenvironments are associated with an increased risk of lung cancer development. It has unexplored effects on the progression of lung cancer malignant progress, a cancer stem cell (CSC) disease. We hypothesized that LF exposure may reprogram the CSC-like potential and metastasis tumorigenicity of lung cancers. Non-small cell lung cancer (NSCLC) cells and transplanted mice were used as the experiment models to test the hypothesis. Cultivation of human NSCLC cell (H23) in an LF microenvironment induced CSC-like properties, which were signified by the increased expression of the CSC surface marker and pluripotency markers. It also induced trans-differentiation and increased the self-renewal ability of oncospheres. The CSC phenotype of LF-H23 cells coincided with a metabolic reprogramming to aerobic glycolysis evidenced by elevated lactate release and medium acidification, the downregulation of pyruvate dehydrogenase E1-α, and an altered redox status according to the NAD+/NADH and NADP+/NADPH ratios. Blockage of the mTOR and Shh signaling reversed the LF-induced Warburg metabolic switch and deactivated the LF-induced mTOR–HIF1 pathway and CSC signatures. Moreover, stemness markers, ALDH1A1, SOX2, OCT4, and embryonic signaling pathway markers, Shh, Gli1, well up-regulated in both short- and long-term culture in the LF medium. NSCLC long-term cultured in LF medium tend to form more and larger oncospheres than the control and short-term groups. C57BL / 6 mice fed on the folate-deficient diet were intrapleurally injected with LF-induced tumor sphere cells, and it was found that only sphere cells with lactate metabolism regulated by LF could cause metastasis of lung cancer in all transplanted mice. All the data indicate the significance of LF microenvironment in the lactate-energy metabolic reprogramming of CSC signatures for promoting the in vitro tumorigenicity and in vivo metastasis of lung cancer cells.