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Open Access 01-12-2023 | Pancreatic Cancer | Research

LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability

Authors: Lijie Han, Yongsheng Jiang, Minmin Shi, Lina Gan, Zhichong Wu, Meilin Xue, Youwei Zhu, Cheng Xiong, Ting Wang, Xiaozhu Lin, Baiyong Shen, Lingxi Jiang, Hao Chen

Published in: Journal of Translational Medicine | Issue 1/2023

Abstract

Background

LIPH, a membrane-associated phosphatidic acid-selective phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear.

Methods

Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy.

Results

LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/AKT/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects.

Conclusion

LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects.

Graphical Abstract

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Title: LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability
Authors: Lijie Han
Yongsheng Jiang
Minmin Shi
Lina Gan
Zhichong Wu
Meilin Xue
Youwei Zhu
Cheng Xiong
Ting Wang
Xiaozhu Lin
Baiyong Shen
Lingxi Jiang
Hao Chen
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-023-04702-6

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Abstract

Background

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