-
Clinical and Translational Medicine Dec 2023Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits...
BACKGROUND
Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous.
METHODS
Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings.
RESULTS
HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC.
CONCLUSIONS
RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
Topics: Humans; Carcinoma, Hepatocellular; Cell Proliferation; Glycolysis; Liver Neoplasms; Phosphoglycerate Mutase
PubMed: 38093528
DOI: 10.1002/ctm2.1511 -
IUBMB Life Oct 2019Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to... (Review)
Review
Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer-specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.
Topics: Cell Proliferation; Glyceric Acids; Glycolysis; Humans; Molecular Targeted Therapy; Neoplasms; Phosphoglycerate Mutase
PubMed: 31169978
DOI: 10.1002/iub.2100 -
BMC Cancer Sep 2023Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a poor prognosis. Identifying biomarkers based on molecular mechanisms is critical for...
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a poor prognosis. Identifying biomarkers based on molecular mechanisms is critical for early diagnosis, timely treatment, and improved prognosis of lung cancer. MALAT1 has been reported to have overexpressed and tumor-promoting functions in NSCLC. It has been proposed as a potential biomarker for the diagnosis and prognosis of cancer. Therefore, this study was conducted to profile the changes in gene expression according to the regulation of expression of MALAT1 in NSCLC cell lines and to investigate the correlation through bioinformatic analysis of differentially expressed genes (DEGs).
METHODS
MALAT1 expression levels were measured using RT-qPCR. The biological functions of MALAT1 in NSCLC were analyzed by cell counting, colony forming, wound-healing, and Transwell invasion assays. In addition, gene expression profiling in response to the knockdown of MALAT1 was analyzed by transcriptome sequencing, and differentially expressed genes regulated by MALAT1 were performed by GO and KEGG pathway enrichment analyses. Bioinformatic databases were used for gene expression analysis and overall survival analysis.
RESULTS
Comparative analysis versus MALAT1 expression in MRC5 cells (a normal lung cell line) and the three NSCLC cell lines showed that MALAT1 expression was significantly higher in the NSCLC cells. MALAT1 knockdown decreased cell survival, proliferation, migration, and invasion in all three NSCLC cell lines. RNA-seq analysis of DEGs in NSCLC cells showed 198 DEGs were upregulated and 266 DEGs downregulated by MALAT1 knockdown in all three NSCLC cell lines. Survival analysis on these common DEGs performed using the OncoLnc database resulted in the selection of five DEGs, phosphoglycerate mutase 1 (PGAM1), phosphoglycerate mutase 4 (PGAM4), nucleolar protein 6 (NOL6), nucleosome assembly protein 1 like 5 (NAP1L5), and sestrin1 (SESN1). The gene expression levels of these selected DEGs were proved to gene expression analysis using the TNMplot database.
CONCLUSION
MALAT1 might function as an oncogene that enhances NSCLC cell survival, proliferation, colony formation, and invasion. RNA-seq and bioinformatic analyses resulted in the selection of five DEGs, PGAM1, PGAM4, NOL6, NAP1L5, and SESN1, which were found to be closely related to patient survival and tumorigenesis. We believe that further investigation of these five DEGs will provide valuable information on the oncogenic role of MALAT1 in NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gene Expression Profiling; Lung Neoplasms; Phosphoglycerate Mutase; RNA, Long Noncoding
PubMed: 37667226
DOI: 10.1186/s12885-023-11347-7 -
Frontiers in Immunology 2023Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate...
INTRODUCTION
Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.
OBJECTIVES
This study investigated the association between PGAM5 and gut microbiota in mice with TBI.
METHODS
The controlled cortical impact injury was established in mice with genetically-ablated () or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male mice or (). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.
RESULTS
Treated with antibiotics for suppressing gut microbiota in mice partially relieved the role of deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. knockout exhibited an increased abundance of in mice. FMT from male mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.
CONCLUSION
Thus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with -Nlrp3 contributing to peripheral effects.
Topics: Male; Animals; Mice; Neuroprotection; Neuroinflammatory Diseases; Phosphoglycerate Mutase; Verrucomicrobia; Brain Injuries, Traumatic; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37287985
DOI: 10.3389/fimmu.2023.1172710 -
Asian Journal of Andrology 2018Phosphoglycerate mutase 1 (PGAM1) is upregulated in many cancer types and involved in cell proliferation, migration, invasion, and apoptosis. However, the relationship...
Phosphoglycerate mutase 1 (PGAM1) is upregulated in many cancer types and involved in cell proliferation, migration, invasion, and apoptosis. However, the relationship between PGAM1 and prostate cancer is poorly understood. The present study investigated the changes in PGAM1 expression in prostate cancer tissues compared with normal prostate tissues and examined the cellular function of PGAM1 and its relationship with clinicopathological variables. Immunohistochemistry and Western blotting revealed that PGAM1 expression was upregulated in prostate cancer tissues and cell lines. PGAM1 expression was associated with Gleason score (P = 0.01) and T-stage (P = 0.009). Knockdown of PGAM1 by siRNA in PC-3 and 22Rv1 prostate cancer cell lines inhibited cell proliferation, migration, and invasion and enhanced cancer cell apoptosis. In a nude mouse xenograft model, PGAM1 knockdown markedly suppressed tumor growth. Deletion of PGAM1 resulted in decreased expression of Bcl-2, enhanced expression of Bax, caspases-3 and inhibition of MMP-2 and MMP-9 expression. Our results indicate that PGAM1 may play an important role in prostate cancer progression and aggressiveness, and that it might be a valuable marker of poor prognosis and a potential therapeutic target for prostate cancer.
Topics: Animals; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Deletion; Gene Knockdown Techniques; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; PC-3 Cells; Phosphoglycerate Mutase; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Transplantation, Heterologous; bcl-2-Associated X Protein
PubMed: 29271400
DOI: 10.4103/aja.aja_57_17 -
The inhibition of PGAM5 suppresses seizures in a kainate-induced epilepsy model mitophagy reduction.Frontiers in Molecular Neuroscience 2022Epilepsy is a common neurological disease, and excessive mitophagy is considered as one of the major triggers of epilepsy. Mitophagy is a crucial pathway affecting...
BACKGROUND
Epilepsy is a common neurological disease, and excessive mitophagy is considered as one of the major triggers of epilepsy. Mitophagy is a crucial pathway affecting reactive oxygen species. Phosphoglycerate mutase 5 (PGAM5) is a protein phosphatase present in mitochondria that regulates many biological processes including mitophagy and cell death. However, the mechanism of PGAM5 in epilepsy remains unclear. The purpose of the present study was to examine whether PGAM5 affects epilepsy through PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy.
METHODS
After the knockdown of PGAM5 expression by the adeno-associated virus, an epilepsy model was created by kainic acid. Next, the seizure activity was recorded by local field potentials before evaluating the level of mitochondrial autophagy marker proteins. Lastly, the ultrastructure of mitochondria, neuronal damage and oxidative stress levels were further observed.
RESULTS
A higher PGAM5 level was found in epilepsy, and its cellular localization was in neurons. The interactions between PGAM5 and PINK1 in epilepsy were further found. After the knockdown of PGAM5, the level of PINK1 and light chain 3B was decreased and the expression of the translocase of the inner mitochondrial membrane 23 and translocase of the outer mitochondrial membrane 20 were both increased. Knockdown of PGAM5 also resulted in reduced neuronal damage, decreased malondialdehyde levels, decreased reactive oxygen species production and increased superoxide dismutase activity. In addition, the duration of spontaneous seizure-like events (SLEs), the number of SLEs and the time spent in SLEs were all reduced in the epilepsy model after inhibition of PGAM5 expression.
CONCLUSION
Inhibition of PGAM5 expression reduces seizures inhibiting PINK1-mediated mitophagy.
PubMed: 36618822
DOI: 10.3389/fnmol.2022.1047801 -
Cancers Sep 2023Phosphoglycerate mutase 5 (PGAM5) is a Ser/His/Thr phosphatase responsible for regulating mitochondrial homeostasis. Overexpression of PGAM5 is correlated with a poor...
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 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, 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.
PubMed: 37835490
DOI: 10.3390/cancers15194796 -
World Journal of Clinical Cases May 2022Drugs targeting mitochondria can induce mitophagy and restrain proliferation in colorectal cancer (CRC) cells. Phosphoglycerate mutase family member 5 (PGAM5) activates...
BACKGROUND
Drugs targeting mitochondria can induce mitophagy and restrain proliferation in colorectal cancer (CRC) cells. Phosphoglycerate mutase family member 5 (PGAM5) activates serine/threonine PTEN-induced putative kinase 1/Parkin pathway-mediated mitophagy. However, there are few studies on the clinical and prognostic significance of expression of PGAM5 protein and mitophagy-related protein Parkin in patients.
AIM
To assess the clinical significance of PGAM5 and Parkin proteins, as biomarkers for diagnosis and prognosis of CRC, by studying their expression in advanced CRC tissues and their association with clinicopathological parameters.
METHODS
The expression of PGAM5 and Parkin in CRC tissues from 100 patients was determined by immunohistochemistry. Each case was evaluated by using a combined scoring method based on signal intensity staining (scored 0-3) and the proportion of positively stained cancer cells (scored 0-4). The final staining score was calculated as the intensity score multiplied by the proportion score. Specimens were categorized as either high or low expression according to the Youden index, and the association between the expression of PGAM5 or Parkin and clinicopathological factors was ascertained. Additionally, we employed western blot to measure PGAM5 and Parkin protein expression in six matched pairs of CRC and adjacent non-tumor tissues.
RESULTS
Immunohistochemical and western blot findings showed that both PGAM5 and Parkin protein expression in tumor tissues was significantly higher than that in the adjacent tissues: PGAM5 and Parkin were mainly expressed in the cytoplasm of colonic epithelial cells. PGAM5 and Parkin protein levels were significantly positively correlated in advanced CRC tissues. Moreover, reduced Parkin protein expression was an independent prognostic factor for overall survival and progression-free survival in CRC patients as evinced by multivariate analysis.
CONCLUSION
The expression of PGAM5 protein and mitophagy-related protein Parkin has diagnostic significance for CRC and may become new biomarkers. Parkin may be a potential marker for the survival of CRC patients.
PubMed: 35663086
DOI: 10.12998/wjcc.v10.i14.4368 -
Cell Death Discovery Mar 2023Oxeiptosis is a recently identified reactive oxygen species (ROS)-sensitive, caspase independent, non-inflammatory regulated cell death pathway. The activation of...
Oxeiptosis is a recently identified reactive oxygen species (ROS)-sensitive, caspase independent, non-inflammatory regulated cell death pathway. The activation of Kelch-like ECH-associated protein 1-Phosphoglycerate mutase 5-Apoptosis inducing factor mitochondria associated 1 (KEAP1-PGAM5-AIFM1) pathway is the key signaling event in the execution of oxeiptosis. In the present study, we demonstrate that sanguinarine (SNG), a quaternary benzophenanthridine alkaloid, induces oxeiptosis in human colorectal cancer (CRC) cells via ROS, specifically hydrogen peroxide (HO)-dependent activation of KEAP1-PGAM5-AIFM1 signaling axis. Whilst, knockdown of KEAP1, PGAM5, and AIFM1 largely abolishes SNG-induced oxeiptosis, hence reinforcing the importance of the role of this pathway in the SNG-mediated cytotoxicity. Moreover, extracellular addition of HO sensitizes SNG-induced oxeiptosis in CRC cells, while removal of intracellular ROS by ROS scavengers, not only alleviated the overproduction of ROS caused by SNG, but also reversed the biochemical events associated with oxeiptosis. Finally, in vivo study demonstrates that SNG effectively reduces the tumor growth in HT-29 xenograft mouse model through features associated with oxeiptosis. This study highlights oxeiptosis as a novel tumor suppressive mechanism and further investigation of the role of oxeiptosis in cancer treatment is warranted.
PubMed: 36914635
DOI: 10.1038/s41420-023-01376-3 -
Acta Biochimica Et Biophysica Sinica Aug 2023Tumor metabolic reprogramming and epigenetic modification work together to promote tumorigenesis and development. Protein lysine acetylation, which affects a variety of...
Tumor metabolic reprogramming and epigenetic modification work together to promote tumorigenesis and development. Protein lysine acetylation, which affects a variety of biological functions of proteins, plays an important role under physiological and pathological conditions. Here, through immunoprecipitation and mass spectrum data, we show that phosphoglycerate mutase 5 (PGAM5) deacetylation enhances malic enzyme 1 (ME1) metabolic enzyme activity to promote lipid synthesis and proliferation of liver cancer cells. Mechanistically, we demonstrate that the deacetylase SIRT2 mediates PGAM5 deacetylation to activate ME1 activity, leading to ME1 dephosphorylation, subsequent lipid accumulation and the proliferation of liver cancer cells. Taken together, our study establishes an important role for the SIRT2-PGAM5-ME1 axis in the proliferation of liver cancer cells, suggesting a potential innovative cancer therapy.
Topics: Humans; Sirtuin 2; Lipid Metabolism; Phosphoglycerate Mutase; Liver Neoplasms; Cell Proliferation; Lipids; Acetylation; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 37580952
DOI: 10.3724/abbs.2023155