Purpose: Metabolic reprogramming is frequently identified in hepatocellular carcinoma, which is the most common type of liver malignancy. The reprogrammed cellular metabolisms promote tumor cell survival, proliferation, angiogenesis and metastasis. However, the mechanisms of this process remain unclear in hepatocellular carcinoma. Experimental Design: Theglobal non-targeted metabolic studyin 69 paired hepatic carcinomas and adjacent tissue specimens were performed using capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based approach. Key findings were validated by targeted metabolomic approach. Biological studies were also performed to investigate the role of proline biosynthesis in HCC pathogenesis. Results: Proline metabolism wasmarkedly changed in HCC tumor tissue, characterized withaccelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoproteinlevels and poor prognosisin HCC.In addition, we found that hydroxyproline promoted hypoxia- and HIF-dependent phenotype in HCC. Moreover, we demonstrated that hypoxia activated proline biosynthesis via upregulation of ALDH18A, subsequently leading to accumulation of hydroxyproline via attenuated PRODH2 activity. More importantly, we showed that glutamine, proline and hydroxyproline metabolic axis supported HCC cell survival through modulating HIF1α stability in response to hypoxia. Finally, Inhibition of proline biosynthesis significantly enhanced cytotoxicity of sorafenib in vitro and in vivo. Conclusions: Our results demonstrate that hypoxic microenvironment activates proline metabolism, resulting in accumulation of hydroxyproline that promotes HCC tumor progression and sorafenib resistance through modulating HIF1α. These findings provide the proof of concept for targeting proline metabolism as a potential therapeutic strategy for hepatocellular carcinoma.
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