PGAM5 promotes tumorigenesis of gastric cancer cells through PI3K/AKT pathway

Meng, Lei; Hu, Pibo; Xu, A-Man

doi:10.1016/j.prp.2023.154405

Cited by 6 publications

(4 citation statements)

References 35 publications

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“…Two other phosphohistidine phosphatases, PHPT1 (12–15) and PGAM5 (16, 17), have also been implicated in promoting tumorigenesis. However, unlike PHPT1 and PGAM5, structural analysis suggests that the LHPP catalytic site is not accessible to large proteins, and may only be accessible to small phosphate-containing molecules, like other phosphatases in the HAD family (46), most of which only act on small molecules and not phosphoproteins (46).…”

Section: Discussionmentioning

confidence: 99%

“…PHPT1 has been reported to be upregulated in lung cancer patients and cell lines (12, 13), associated with decreased proliferation in hepatocellular carcinoma (14), and increased levels have been linked to lower overall survival in clear-cell RCC patients (15). PGAM5, on the other hand, is upregulated in liver cancer and its knockout inhibits the proliferation, migration, and invasion of gastric cancer cells (16, 17). Only the histidine kinase NME1 has been studied in breast cancer, where it was shown to inhibit the migration of breast cancer cell lines (18).…”

Section: Introductionmentioning

confidence: 99%

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LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

Reina,

Vallmajo-Martin,

Ning

et al. 2024

Preprint

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Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP's role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

Reina,

Vallmajo-Martin,

Ning

et al. 2024

Preprint

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“…Epidemiological estimates indicate that greater than 1 million people will be diagnosed with HCC by 2025 [1,2]. Overexpression of tumoral phosphoglycerate mutase 5 (PGAM5) is correlated with reduced survival in hepatocellular carcinoma, as well as other cancers [3][4][5][6][7][8]. The mitochondrial membrane protein PGAM5 is a serine/threonine/histidine phosphatase with a diverse set of substrates [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of tumoral phosphoglycerate mutase 5 (PGAM5) is correlated with reduced survival in hepatocellular carcinoma, as well as other cancers [3][4][5][6][7][8]. The mitochondrial membrane protein PGAM5 is a serine/threonine/histidine phosphatase with a diverse set of substrates [6][7][8][9][10][11]. Among these are mediators of mitophagy and multiple regulated cell death pathways [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Deletion of PGAM5 Downregulates FABP1 and Attenuates Long-Chain Fatty Acid Uptake in Hepatocellular Carcinoma

Muthusamy,

Liu,

Johnston

2023

Cancers

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Phosphoglycerate mutase 5 (PGAM5) is a Ser/His/Thr phosphatase responsible for regulating mitochondrial homeostasis. Overexpression of PGAM5 is correlated with a poor prognosis in hepatocellular carcinoma, colon cancer, and melanoma. In hepatocellular carcinoma, silencing of PGAM5 reduces growth, which has been attributed to decreased mitophagy and enhanced apoptosis. Yet in colon cancer, PGAM5’s pro-tumor survival effect is correlated to lipid metabolism. We sought to identify whether deletion of PGAM5 modulated lipid droplet accrual in hepatocellular carcinoma. HepG2 and Huh7 PGAM5 knockout cell lines generated using CRISPR/Cas9 technology were used to measure cell growth, cellular ATP, and long-chain fatty acid uptake. Expression of hepatocellular fatty acid transporters, cluster of differentiation 36 (CD36), solute carrier family 27 member 2 (SLC27A2), solute carrier family 27 member 5 (SLC27A5), and fatty acid binding protein 1 (FABP1) was measured by quantitative PCR and Western blot. We found that deletion of PGAM5 attenuates hepatocellular carcinoma cell growth and ATP production. Further, PGAM5 knockout ameliorates palmitate-induced steatosis and reduces expression of FABP1 in HepG2 and Huh7 cell lines. PGAM5’s role in hepatocellular carcinoma includes regulation of fatty acid metabolism, which may be related to expression of the fatty acid transporter, FABP1.

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Ponicidin Promotes Hepatocellular Carcinoma Mitochondrial Apoptosis by Stabilizing Keap1‐PGAM5 Complex

Zhao,

Liang,

Zhang

et al. 2024

Advanced Science

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Ponicidin is a diterpenoid with demonstrated antitumor activity in clinical trials. However, the specific function and mechanism of action against hepatocellular carcinoma (HCC) remain unknown. In this study, it is found that ponicidin significantly inhibited the proliferation and migration of HCC cells. It is shown that ponicidin targets Keap1 and promotes the formation of the Keap1‐PGAM5 complex, leading to the ubiquitination of PGAM5, using biotin‐labeled ponicidin for target fishing and the HuProtTM Human Proteome Microarray V4.0. Ponicidin is found to activate the cysteine‐dependent mitochondrial pathway via PGAM5, resulting in mitochondrial damage and ROS production, thereby promoting mitochondrial apoptosis in HepG2 cells. The first in vitro cocrystal structure of the PGAM5 IE 12‐mer peptide and the Keap1 Kelch domain is obtained. Using molecular dynamics simulations to confirm the binding of ponicidin to the Keap1‐PGAM5 complex. Based on the depth‐based dynamic simulation, it is found that ponicidin can induce the tightening of the Keap1‐PGAM5 interaction pocket, thereby stabilizing the formation of the protein complex. Finally, it is observed that ponicidin effectively inhibited tumor growth and promoted tumor cell apoptosis in a BALB/c nude mouse xenograft tumor model. The results provide insight into the anti‐HCC properties of ponicidin based on a mechanism involving the Keap1‐PGAM5 complex.

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PGAM5 promotes tumorigenesis of gastric cancer cells through PI3K/AKT pathway

Cited by 6 publications

References 35 publications

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

Deletion of PGAM5 Downregulates FABP1 and Attenuates Long-Chain Fatty Acid Uptake in Hepatocellular Carcinoma

Ponicidin Promotes Hepatocellular Carcinoma Mitochondrial Apoptosis by Stabilizing Keap1‐PGAM5 Complex

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