Global Metabolic Profiling Identifies a Pivotal Role of Proline and Hydroxyproline Metabolism in Supporting Hypoxic Response in Hepatocellular Carcinoma
Global Metabolic Profiling Identifies a Pivotal Role of Proline and Hydroxyproline Metabolism in Supporting Hypoxic Response in Hepatocellular Carcinoma
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整体代谢分析确定了脯氨酸和羟脯氨酸代谢在支持肝细胞癌缺氧反应中的关键作用
DOI：
10.1158/1078-0432.ccr-17-1707
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发表时间：
2018-01-15
影响因子：
11.5
通讯作者：
Liu, Yang
中科院分区：
文献类型：
--
作者：
Tang, Ling;Zeng, Jun;Liu, Yang
目的：肝细胞癌（HCC）是最常见的肝脏恶性肿瘤，其代谢重编程是常见的。重编程的细胞代谢促进肿瘤细胞存活、增殖、血管生成和转移。然而，这一过程的机制在HCC中仍不清楚。实验设计：采用毛细管电泳-飞行时间质谱法对69例肝癌及癌旁组织标本进行了整体非靶向代谢研究。通过靶向代谢组学方法验证了关键发现。生物学研究也被用来调查脯氨酸生物合成在肝癌发病机制中的作用。结果如下：肝癌组织中脯氨酸代谢发生明显改变，表现为脯氨酸消耗加快和羟脯氨酸蓄积，与甲胎蛋白水平及预后密切相关。此外，我们发现羟脯氨酸促进肝癌的缺氧和HIF依赖性表型。此外，我们证明缺氧通过上调ALDH 18 A1激活脯氨酸的生物合成，随后通过减弱PRODH 2活性导致羟脯氨酸的积累。更重要的是，我们发现谷氨酰胺、脯氨酸和羟脯氨酸代谢轴通过调节HIF 1 α在缺氧时的稳定性来支持HCC细胞的存活。最后，脯氨酸生物合成的抑制显着增强索拉非尼在体外和体内的细胞毒性。结论：我们的研究结果表明，缺氧微环境激活脯氨酸代谢，导致羟脯氨酸的积累，促进HCC肿瘤进展和索拉非尼耐药，通过调节HIF 1 α。这些发现为靶向脯氨酸代谢作为HCC的潜在治疗策略提供了概念证据。Clin Cancer Res; 24（2）; 474-85.©2017 AACR.
Purpose: 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. Experimental Design: 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. Results: 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 ALDH18A1, 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 HCC. Clin Cancer Res; 24(2); 474–85. ©2017 AACR.