Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E
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...
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doaj-12e5df7ab7c4431e8de3fee272de07632020-11-25T02:10:05ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-02-0138111510.1186/s13046-019-1053-yPhosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4EXuhui Ma0Boya Li1Jie Liu2Yan Fu3Yongzhang Luo4The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua UniversityThe National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua UniversityThe National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua UniversityThe National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua UniversityThe National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua UniversityAbstract 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 13C6 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.http://link.springer.com/article/10.1186/s13046-019-1053-yPHGDHeIF4A1eIF4ETranslation initiationPancreatic cancer development |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xuhui Ma Boya Li Jie Liu Yan Fu Yongzhang Luo |
spellingShingle |
Xuhui Ma Boya Li Jie Liu Yan Fu Yongzhang Luo Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E Journal of Experimental & Clinical Cancer Research PHGDH eIF4A1 eIF4E Translation initiation Pancreatic cancer development |
author_facet |
Xuhui Ma Boya Li Jie Liu Yan Fu Yongzhang Luo |
author_sort |
Xuhui Ma |
title |
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E |
title_short |
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E |
title_full |
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E |
title_fullStr |
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E |
title_full_unstemmed |
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E |
title_sort |
phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eif4a1 and eif4e |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-02-01 |
description |
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 13C6 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. |
topic |
PHGDH eIF4A1 eIF4E Translation initiation Pancreatic cancer development |
url |
http://link.springer.com/article/10.1186/s13046-019-1053-y |
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