Global Metabolic Profiling Identifies a Pivotal Role of Proline and Hydroxyproline Metabolism in Supporting Hypoxic Response in Hepatocellular Carcinoma

Abstract

Metabolic reprogramming is frequently identified in hepatocellular carcinoma (HCC), 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 HCC. The global nontargeted metabolic study in 69 paired hepatic carcinomas and adjacent tissue specimens was performed using capillary electrophoresis-time of flight mass spectrometry-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. Proline metabolism was markedly changed in HCC tumor tissue, characterized with accelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoprotein levels and poor prognosis in 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 , subsequently leading to accumulation of hydroxyproline via attenuated 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 and 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 HCC. .

Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer

“…Additionally, altered proline metabolism in the form of increased degradation and reduced biosynthesis appears to be another prominent NEPC‐associated metabolic feature. Further investigations into how these changes facilitate NEPC development could be a promising area of research, especially given its contribution to metastasis and the hypoxic response . It has also been suggested that in prostatic tumors containing a mixture of NE and adenocarcinoma cells, certain paracrine factors secreted by NE cells could facilitate the growth and aggressiveness of neighboring adenocarcinoma cells .…”

“…Further investigations into how these changes facilitate NEPC development could be a promising area of research, especially given its contribution to metastasis and the hypoxic response. 13,14 It has also been suggested that in prostatic tumors containing a mixture of NE and adenocarcinoma cells, certain paracrine factors secreted by NE cells could facilitate the growth and aggressiveness of neighboring adenocarcinoma cells. 15,16 Whether the increased secretion of lactic acid from NE cells could function in an analogous paracrine fashion to enhance PCa aggressiveness would be an intriguing area for further study.…”

Glutamine synthetase promotes tumor invasion in hepatocellular carcinoma through mediating epithelial–mesenchymal transition

“…Glutamine synthetase (GS) is involved in glutamine metabolism in favor of tumors, including HCC . Christa et al .…”

“…Glutamine synthetase (GS) is involved in glutamine metabolism in favor of tumors, including HCC. [8][9][10][11] Christa et al reported for the first time that the expression of GS in HCC tissue is higher than that in para-tumor tissue. 12 The expression level of GS elevates gradually during malignant transformation of hepatic lesion and progression of HCC.…”

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

“…On the other hand, metabolic enzymes also have a direct role in regulating transcription and translation in response to hypoxia and sorafenib treatment [45]. Proline and hydroxyproline metabolism could modulate HIF1a stability through inhibiting hydroxylation of HIF1a protein and subsequent pVHL-mediated degradation [82]. Other post-translational modifications of HIF family including SUMOylation and ubiquitination have also been well studied under SIH in HCC [20,23].…”