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

by Selleckchem | Jan 05 2024

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.

Comments:

This study provides crucial insights into the role of LIPH in pancreatic ductal adenocarcinoma (PDAC) progression and its potential as a therapeutic target. LIPH, by modulating the LPA/LPAR axis and stabilizing ALDOA in the cytosol, seems to play a pivotal role in stimulating glycolysis and glycerolipid synthesis, thereby promoting PDAC proliferation and progression.

The findings suggest that targeting LIPH could offer a promising therapeutic strategy. The identified gemcitabine-based combination therapy involving ki16425 and aldometanib, tailored to PDAC with high LIPH expression, demonstrates efficacy in preclinical models while minimizing side effects. This approach appears to disrupt aberrant glycolysis and could potentially enhance the response to treatment.

Further research and clinical trials will likely be necessary to validate these findings and explore the therapeutic potential of targeting LIPH in PDAC. Understanding the intricate mechanisms by which LIPH influences PDAC biology may pave the way for more effective and targeted therapies in combating this challenging disease.