Phosphoglycerate Dehydrogenase Promotes Pancreatic Cancer Development by Interacting with EIF4A1 and EIF4E

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Feb 13

PMID 30744688

Citations 41

Authors

Xuhui Ma

Boya Li

Jie Liu

Yan Fu

Yongzhang Luo

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53.

Li D, Hu X, Tian Z, Ning Q, Liu J, Yue Y Acta Pharmacol Sin. 2025; .

PMID: 39856433 DOI: 10.1038/s41401-024-01467-6.

Correction: Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E.

Ma X, Li B, Liu J, Fu Y, Luo Y J Exp Clin Cancer Res. 2024; 43(1):328.

PMID: 39710704 PMC: 11665198. DOI: 10.1186/s13046-024-03252-z.

Non-canonical function of PHGDH promotes HCC metastasis by interacting with METTL3.

Cheng B, Ma J, Tang N, Liu R, Peng P, Wang K Cell Oncol (Dordr). 2024; 47(6):2427-2438.

PMID: 39695045 DOI: 10.1007/s13402-024-01029-2.

PHGDH Induction by MAPK Is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.

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Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity.

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