Fructose utilization enhanced by GLUT5 promotes lung cancer cell migration via activating glycolysis/AKT pathway.

Jing Yang, Changsheng Dong, Jia Wu, Dan Liu, Qin Luo, Xing Jin

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2023 Apr

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Lung cancer is the leading cause of cancer-related mortalities worldwide, and metastasis contributes to a large number of deaths in lung carcinoma patients. New approaches for anti-metastatic treatment are urgently needed. Enhanced fructose metabolism mediated by GLUT5 directly contributes to cancer metastasis. However, the underlying mechanism remains to be elucidated, which we aimed to explore in this study. The overexpression and knockdown of SLC2A5, the encoding gene of GLUT5, were established by retrovirus system and CRISPR/Cas9 technology, respectively. Cell migration was conducted by trans-well assay. Western blotting assay was carried out to detect the expression of GLUT5, total AKT, phosphorylated AKT (pAKT-S473 and pAKT-T308) and LDHA. Lactate production was measured by colorimetric assay. Experimental lung metastasis model by tail vein injection was constructed to evaluate the metastatic potential of GLUT5 in vivo. Overexpression of SLC2A5 promoted migration of lung cancer cells both in vitro and in vivo, and shortened the overall survival of mice. While, SLC2A5 deletion blocked the migration of lung cancer cells. GLUT5-mediated fructose utilization upregulated phosphorylated AKT, which was responsible for enhanced migration of lung cancer cells. Additionally, GLUT5-mediated fructose utilization boosted glycolysis with overproduction of lactate, resulting in upregulation of phosphorylated AKT. Moreover, lung cancer cell migration and AKT activation were restrained by glycolysis inhibitor 2-deoxy-D-glucose (2-DG) or GLUT5-specific inhibitor 2,5-anhydro-D-mannitol (2,5-AM). Our study unveils glycolysis/lactate/AKT pathway is responsible for lung cancer cell migration induced by GLUT5-mediated fructose metabolism, providing a potential therapeutic avenue for lung cancer metastasis. © 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).

Citation

Jing Yang, Changsheng Dong, Jia Wu, Dan Liu, Qin Luo, Xing Jin. Fructose utilization enhanced by GLUT5 promotes lung cancer cell migration via activating glycolysis/AKT pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2023 Apr;25(4):1080-1090