磷酸甘油酸脱氢酶通过与 eIF4A1 和 eIF4E 相互作用促进胰腺癌的发展。
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E.
机构信息
The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing, 100084, China.
Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, 100084, China.
出版信息
J Exp Clin Cancer Res. 2019 Feb 11;38(1):66. doi: 10.1186/s13046-019-1053-y.
BACKGROUND
Pancreatic cancer is one of the most malignant cancers. The overall 5-year survival rate of its patients is 8%, the lowest among major cancer types. It is very urgent to study the development mechanisms of this cancer and provide potential targets for therapeutics design. Glucose, one of the most essential nutrients, is highly exploited for aerobic glycolysis in tumor cells to provide building blocks. However, the glucose consumption manner in pancreatic cancer cells is unclear. And the mechanism of the substantial metabolic pathway promoting pancreatic cancer development is also unrevealed.
METHODS
C glucose was used to trace the glucose carbon flux and detected by mass spectrum. The expressions of PHGDH were determined in cells and pancreatic adenocarcinomas. Knockdown and overexpression were performed to investigate the roles of PHGDH on pancreatic cancer cell proliferation, colony formation and tumor growth. The mechanisms of PHGDH promoting pancreatic cancer development were studied by identifying the interacting proteins and detecting the regulatory functions on translation initiations.
RESULTS
Pancreatic cancer cells PANC-1 consumed large amounts of glucose in the serine and glycine de novo synthesis. Phosphoglycerate dehydrogenase (PHGDH) highly expressed and controlled this pathway. Knockdown of PHGDH significantly attenuated the tumor growth and prolonged the survival of tumor bearing mice. The pancreatic adenocarcinoma patients with low PHGDH expression had better overall survival. Mechanistically, knockdown of PHGDH inhibited cell proliferation and tumorigenesis through disrupting the cell-cell tight junctions and the related proteins expression. Besides catalyzing serine synthesis to activate AKT pathway, PHGDH was found to interact with the translation initiation factors eIF4A1 and eIF4E and facilitated the assembly of the complex eIF4F on 5' mRNA structure to promote the relevant proteins expression.
CONCLUSION
Besides catalyzing serine synthesis, PHGDH promotes pancreatic cancer development through enhancing the translation initiations by interacting with eIF4A1 and eIF4E. Inhibiting the interactions of PHGDH/eIF4A1 and PHGDH/eIF4E will provide potential targets for anti-tumor therapeutics development.
背景
胰腺癌是最恶性的癌症之一。其患者的总体 5 年生存率仅为 8%，在主要癌症类型中最低。因此，研究这种癌症的发展机制并为治疗设计提供潜在靶点非常紧迫。葡萄糖是最基本的营养物质之一，在肿瘤细胞中高度用于有氧糖酵解以提供构建块。然而，尚不清楚胰腺癌细胞中葡萄糖的消耗方式。此外，大量代谢途径促进胰腺癌发展的机制也尚未揭示。
方法
使用 C 葡萄糖追踪葡萄糖碳通量，并通过质谱检测。在细胞和胰腺腺癌中测定 PHGDH 的表达。通过敲低和过表达来研究 PHGDH 对胰腺癌细胞增殖、集落形成和肿瘤生长的作用。通过鉴定相互作用蛋白并检测对翻译起始的调节功能来研究 PHGDH 促进胰腺癌发展的机制。
结果
胰腺癌细胞 PANC-1 在丝氨酸和甘氨酸从头合成中大量消耗葡萄糖。磷酸甘油酸脱氢酶（PHGDH）高表达并控制此途径。敲低 PHGDH 可显著减弱肿瘤生长并延长荷瘤小鼠的存活时间。PHGDH 低表达的胰腺腺癌患者总体生存率更好。在机制上，敲低 PHGDH 通过破坏细胞-细胞紧密连接和相关蛋白表达来抑制细胞增殖和肿瘤发生。除了催化丝氨酸合成以激活 AKT 途径外，PHGDH 还被发现与翻译起始因子 eIF4A1 和 eIF4E 相互作用，并促进复合物 eIF4F 在 5' mRNA 结构上的组装，以促进相关蛋白的表达。
结论
除了催化丝氨酸合成外，PHGDH 通过与 eIF4A1 和 eIF4E 相互作用促进胰腺癌的发展，从而增强翻译起始。抑制 PHGDH/eIF4A1 和 PHGDH/eIF4E 的相互作用将为抗肿瘤治疗的发展提供潜在靶点。
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