PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities

Wang, Jin Xiang Kai; Tang, Ni

doi:10.1016/j.gendis.2022.02.010

Cited by 12 publications

(10 citation statements)

References 112 publications

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“…To further explore the effect of Pck1 on AP pathogenesis, we applied 3‐MPA (20 mg/kg) to inhibit Pck1 in AP mice (Figure 3A). 3‐MPA inhibits the activity of Pck1 via restricting the reaction of OAA decarboxylation to PEP and reducing the affinity of Pck1 for guanosine triphosphate (GTP) 18 . There was no significant difference in injury of pancreas or ileum between CON and 3‐MPA groups ( p > .05) (Figure 3B–F).…”

Section: Resultsmentioning

confidence: 95%

“…3-Mercaptopicolinic acid hydrochloride (3-MPA, MCE, China), the inhibitor of Pck1, was applied in mice to investigate the role of Pck1 in IECs during AP. 18 A pilot study was performed to assess its effect and optimal intervention regimens. AP was induced by L-arginine, as previously described.…”

Section: Experimental Designmentioning

confidence: 99%

“…Pck1 plays a crucial role in energy metabolism by facilitating the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP). It has been reported to be modulated by various stress signals, such as inflammation, hypoxia, nutritional alterations, and oxidative 14–18 . Previous studies have indicated that Pck1 was expressed in IECs and increased during experimental colitis and parasitic infections 19,20 …”

Section: Introductionmentioning

confidence: 99%

“…It has been reported to be modulated by various stress signals, such as inflammation, hypoxia, nutritional alterations, and oxidative. [14][15][16][17][18] Previous studies have indicated that Pck1 was expressed in IECs and increased during experimental colitis and parasitic infections. 19,20 The purpose of this study was to explore the effect of Pck1 in IECs during AP and its potential impact on intestinal homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis

Yin,

Xu,

Huang

et al. 2024

The FASEB Journal

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Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L‐arginine‐induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up‐regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D‐lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C‐reactive protein. Inhibition of Pck1 by 3‐Mercaptopicolinic acid hydrochloride (3‐MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3‐MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D‐lactate, endotoxin, and FITC‐Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3‐MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3‐MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

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Section: Resultsmentioning

confidence: 95%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis

Yin,

Xu,

Huang

et al. 2024

The FASEB Journal

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“…36 Emerging evidence shows that dysregulated expression of ACSL4 is tightly associated with various diseases, and especially with cancers. 37 The mechanisms of ACSL4 involvement in tumor development may include iron-dependent, non-apoptotic and cell death pathways 38 Phosphoenolpyruvate carboxykinase 1 (PCK1), 39 a key rate-limiting enzyme in gluconeogenesis, catalyzes the conversion of oxaloacetate to phos- diseases. Understanding the molecular mechanisms underlying the interplay between PPARs and oxidative phosphorylation may provide insights into the development of therapeutic strategies for these conditions.…”

Section: Ppar-related Signature and Energy Metabolism Pathwaymentioning

confidence: 99%

Peroxisome proliferator‐activated receptors signature reveal the head and neck squamous cell carcinoma energy metabolism phenotype and clinical outcome

Yao,

Wang,

Zhang

et al. 2023

The Journal of Gene Medicine

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BackgroundPeroxisome proliferator activating receptors (PPARs) are important regulators of nuclear hormone receptor function, and they play a key role in biological processes such as lipid metabolism, inflammation and cell proliferation. However, their role in head and neck squamous cell carcinoma (HNSC) is unclear.MethodsWe used multiple datasets, including TCGA‐HNSC, GSE41613, GSE139324, PRJEB23709 and IMVigor, to perform a comprehensive analysis of PPAR‐related genes in HNSC. Single‐cell sequencing data were preprocessed using Seurat packets, and intercellular communication was analyzed using CellChat packets. Functional enrichment analysis of PPAR‐related genes was performed using ClusterProfile and GSEA. Prognostic models were constructed using LASSO and Cox regression models, and immunohistochemical analyses were performed using human protein mapping (The Human Protein Atlas).ResultsOur single‐cell RNA sequencing analysis revealed distinct cell populations in HNSC, with T cells having the most significant transcriptome differences between tumors and normal tissues. The PPAR features were higher in most cell types in tumor tissues compared with normal tissues. We identified 17 PPAR‐associated differentially expressed genes between tumors and normal tissues. A prognostic model based on seven PPAR‐associated genes was constructed with high accuracy in predicting 1, 2 and 3 year survival in patients with HNSC. In addition, patients with a low risk score had a higher immune score and a higher proportion of T cells, CD8+ T cells and cytotoxic lymphocytes. They also showed higher immune checkpoint gene expression, suggesting that they might benefit from immunotherapy. PPAR‐related genes were found to be closely related to energy metabolism.ConclusionsOur study provides a comprehensive understanding of the role of PPAR related genes in HNSC. The identified PPAR features and constructed prognostic models may serve as potential biomarkers for HNSC prognosis and treatment response. In addition, our study found that PPAR‐related genes can differentiate energy metabolism and distinguish energy metabolic heterogeneity in HNSC, providing new insights into the molecular mechanisms of HNSC progression and therapeutic response.

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ECM Proteins Nidogen‐1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions

Jeyagaran,

Urbanczyk,

Carvajal‐Berrio

et al. 2024

Adv Healthcare Materials

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Transplantation of donor islets of Langerhans is a potential therapeutic approach for patients with diabetes mellitus; however, its success is limited by islet death and dysfunction during the initial hypoxic conditions at the transplantation site. This highlights the need to support the donor islets in the days post‐transplantation until the site is vascularized. It was previously demonstrated that the extracellular matrix (ECM) proteins nidogen‐1 (NID1) and decorin (DCN) improve the functionality and survival of the β‐cell line, EndoC‐βH3, and the viability of human islets post‐isolation. To advance the use of these ECM proteins toward a clinical application and elucidate the mechanisms of action in primary islets, the study assesses the effects of ECM proteins NID1 and DCN on isolated human donor islets cultured in normoxic and hypoxic conditions. NID1‐ and DCN‐treatment restore β‐cell functionality of human donor islets in a hypoxic environment through upregulation of genes involved in glycolytic pathways and reducing DNA fragmentation in hypoxic conditions comparable to normoxic control islets. The results demonstrate that the utilization of NID1 or DCN with islets of Langerhans may have the potential to overcome the hypoxia‐induced cell death observed post‐transplantation and improve transplant outcomes.

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PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities

Cited by 12 publications

References 112 publications

Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis

Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis

Peroxisome proliferator‐activated receptors signature reveal the head and neck squamous cell carcinoma energy metabolism phenotype and clinical outcome

ECM Proteins Nidogen‐1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions

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