GDNF regulates lipid metabolism and glioma growth through RET/ERK/HIF-1/SREBP-1

Cancer cells rewire their metabolism to meet the demands of growth and survival and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. However, the respective mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of glioma are unclear. The present study demonstrated that glial-derived neurotrophic factor (GDNF) is highly expressed in glioma and associated with poor clinical outcomes. In addition, there was a significant correlation between GDNF/rearranged during transfection (RET)/ERK signaling and sterol regulatory element-binding protein-1 (SREBP-1) expression in glioma cells. Pharmacological or genetic inhibition of GDNF-induced RET/ERK activity downregulated SREBP-1 expression and SREBP-1-mediated transcription of lipogenic genes. Additionally, GDNF regulated SREBP-1 activity by promoting hypoxia-inducible factor-1α (HIF-1α) mediated glucose absorption and hexosamine biosynthetic pathway mediated SREBP cleavage-activating protein N-glycosylation. In addition, the inhibition of SREBP-1 reduced the in vitro GDNF-induced glioma cell proliferation. The results elucidated the complex relationship between GDNF/RET/ERK signaling and dysregulated glycolipid-metabolism, which shows great potential to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.