PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation

Zhang, Mingquan; Xiang, Rong; Glorieux, Christophe; Huang, Peng

doi:10.3390/ijms231911721

Cited by 10 publications

(5 citation statements)

References 40 publications

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“… 24 PLA2G2A is associated with esophageal adenocarcinoma and glioblastoma and has been reported to promote fatty acid synthesis and energy metabolism in pancreatic cancer cells with K-ras mutations. 25 SCGB1D2 mutations have been reported in breast and gynecological cancers and are associated with poor prognosis in pancreatic ductal adenocarcinoma. 26 GAGE analysis revealed sets of genes specifically upregulated in the low G6PD group ( table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy

Nakamura,

Magara,

Yoshimitsu

et al. 2024

J Immunother Cancer

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BackgroundEnhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear.MethodsWe conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.ResultsInhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer).ConclusionG6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy

Nakamura,

Magara,

Yoshimitsu

et al. 2024

J Immunother Cancer

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“…The pro- or anti-tumorigenic effects of PLA2G2A appear to be tissue-specific. PLA2G2A is associated with poor survival in patients with esophageal adenocarcinoma [ 14 ], glioblastoma [ 15 ], rectal cancer [ 16 ], and pancreatic ductal adenocarcinoma [ 17 ]. In contrast, high PLA2G2A expression suppresses gastric adenocarcinoma and gastric cancer progression [ 18 , 19 , 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma

Iwabuchi,

Takahashi,

Kawaguchi

et al. 2023

Cancers

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Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.

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“…FASN, a key enzyme in the initial stage of lipid synthesis, combines acetyl‐CoA with malonyl‐CoA and converts them into long‐chain FAs 92 . FASN has been demonstrated to be overexpressed in numerous solid and hematopoietic tumors, including non‐small‐cell lung cancer (NSCLC), 93 breast cancer, 94 pancreatic cancer, 95 and lymphoma 96 . TVB‐2640, the first FASN inhibitor to enter clinical research, displayed a gratifying tolerability profile with no significant gastrointestinal or serum chemical toxicity in a phase I clinical trial (NCT02223247).…”

Section: Inhibiting Ld Anabolism and Catabolism Is One Of The Approac...mentioning

confidence: 99%

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

Cui,

Man,

Tao

et al. 2024

Acta Physiologica

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IntroductionAbnormal lipid metabolism, one of the hallmarks in cancer, has gradually emerged as a novel target for cancer treatment. As organelles that store and release excess lipids, lipid droplets (LDs) resemble “gears” and facilitate cancer development in the body.AimThis review discusses the life cycle of LDs, the relationship between abnormal LDs and cancer hallmarks, and the application of LDs in theragnostic and clinical contexts to provide a contemporary understanding of the role of LDs in cancer.MethodsA systematic literature search was conducted in PubMed and SPORTDiscus. Retrieve and summarize clinical trials of drugs that target proteins associated with LD formation using the Clinical Trials website. Create a schematic diagram of lipid droplets in the tumor microenvironment using Adobe Illustrator.ConclusionAs one of the top ten hallmarks of cancer, abnormal lipid metabolism caused by excessive generation of LDs interrelates with other hallmarks. The crosstalk between excessive LDs and intracellular free fatty acids (FFAs) promotes an inflammatory environment that supports tumor growth. Moreover, LDs contribute to cancer metastasis and cell death resistance in vivo. Statins, as HMGCR inhibitors, are promising to be the pioneering commercially available anti‐cancer drugs that target LD formation.

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PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation

Cited by 10 publications

References 40 publications

Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy

Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy

Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

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