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Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression.

ABSTRACT: Purpose:To determine whether protein kinase C-iota (PKC-iota) is associated with glucose metabolism in non-small-cell lung cancer (NSCLC) and whether its regulatory effect on metabolic and biological changes observed in NSCLC can be mediated by glucose transporter 1 (GLUT1). Patients and methods:Forty-five NSCLC patients underwent combined 18F-fludeoxyglucose (18F-FDG) positron emission tomography and computed tomography (PET/CT) before surgery, and another eighty-one NSCLC patients were followed-up for 1-91 months after tumor resection. The rate of glucose metabolism in NSCLC was quantified by measuring the maximum standardized uptake value (SUVmax) by 18F-FDG PET/CT. PKC-iota and GLUT1 in NSCLC were detected by immunostaining. In vitro, PKC-iota was knocked down, whereas GLUT1 was silenced with or without PKC-iota overexpression to identify the role of PKC-iota in glycolysis. Spearman's rank correlation coefficient was used in the correlation analysis. Kaplan-Meier analysis was used to assess survival duration. Results:There was a positive relationship between PKC-iota expression and SUVmax in NSCLC (r=0.649, P<0.001). PKC-iota expression also showed a positive relationship with GLUT1 in NSCLC tissues (r=0.686, P<0.001). Patients whose NSCLC tissues highly co-expressed PKC-iota and GLUT1 had worse prognosis compared with patients without high co-expression of PKC-iota and GLUT1. In vitro, PKC-iota silencing significantly decreased the expression of GLUT1 and inhibited glucose uptake and glycolysis; c-Myc silencing restrained PKC-iota-mediated GLUT1 elevation; GLUT1 knockdown remarkably suppressed PKC-iota-mediated glycolysis and cell growth. Conclusion:In NSCLC, the rate of glucose metabolism was positively correlated with PKC-iota expression. PKC-iota increased glucose accumulation and glycolysis by upregulating c-Myc/GLUT1 signaling and is thus involved in tumor progression.

SUBMITTER: Liu L

PROVIDER: S-EPMC6646854 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression.

Liu Liu L Lei Bei B Wang Lihua L Chang Cheng C Yang Hao H Liu Jianjun J Huang Gang G Xie Wenhui W

OncoTargets and therapy 20190718

<h4>Purpose</h4>To determine whether protein kinase C-iota (PKC-iota) is associated with glucose metabolism in non-small-cell lung cancer (NSCLC) and whether its regulatory effect on metabolic and biological changes observed in NSCLC can be mediated by glucose transporter 1 (GLUT1).<h4>Patients and methods</h4>Forty-five NSCLC patients underwent combined <sup>18</sup>F-fludeoxyglucose (<sup>18</sup>F-FDG) positron emission tomography and computed tomography (PET/CT) before surgery, and another e ...[more]

PMID: 31410027

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Project description:BackgroundThe protein tyrosine phosphatase H receptor (PTPRH) is known to regulate the occurrence and development of pancreatic and colorectal cancer. However, its association with glycolysis in non-small cell lung cancer (NSCLC) is still unclear. In this study, we aimed to investigate the relationship between PTPRH expression and glucose metabolism and the underlying mechanism of action.MethodsThe expression of PTPRH in NSCLC cells was evaluated by IHC staining, qRT‒PCR and Western blotting. The effect of PTPRH on cell biological behavior was evaluated by colony assays, EdU experiments, Transwell assays, wound healing assays and flow cytometry. Changes in F-18-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolite levels after altering PTPRH expression were detected via a gamma counter and lactic acid tests. The expression of glycolysis-related proteins in NSCLC cells was detected by Western blotting after altering PTPRH expression.ResultsThe results showed that PTPRH was highly expressed in clinical patient tissue samples and closely related to tumor diameter and clinical stage. In addition, PTPRH expression was associated with glycometabolism indexes on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging, the expression level of Ki67 and the expression levels of glycolysis-related proteins. PTPRH altered cell behavior, inhibited apoptosis, and promoted 18F-FDG uptake, lactate production, and the expression of glycolysis-related proteins. In addition, PTPRH modulated the glycometabolism of NSCLC cells via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, as assessed using LY294002 and 740Y-P (an inhibitor and agonist of PI3K, respectively). The same results were validated in vivo using a xenograft tumor model in nude mice. Protein expression levels of PTPRH, glycolysis-related proteins, p-PI3K/PI3K and p-AKT/AKT were measured by IHC staining using a subcutaneous xenograft model in nude mice.ConclusionsIn summary, we report that PTPRH promotes glycolysis, proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC and ultimately promotes tumor progression, which can be regulated by LY294002 and 740Y-P. These results suggest that PTPRH is a potential therapeutic target for NSCLC.

Project description:BackgroundTumor necrosis factor-α-induced protein 8-like 3 (TNFAIP8L3, also called TIPE3) has been shown to activate PI3K-AKT and MEK-ERK pathways. However, the roles of TIPE3 in progression of lung cancer are largely unknown.MethodsImmunohistochemistry and western blotting were carried out to analyze the expression of TIPE3 in lung cancer clinical tissues and cells. TIPE3-overexpressing and knock-down NSCLC cell lines were established by transfer of TIPE3 coding sequence and shRNA, respectively. In vitro functional assays were performed to assess the effects of TIPE3 on proliferation and metastasis of NSCLC cells. Tumor xenograft mouse model was used to examine the roles of TIPE3 in growth of NSCLC cells in vivo. Western blotting, immunofluorescence, and immunohistochemistry were conducted to evaluate the association of TIPE3 and molecules related to AKT/ERK1/2-GSK3β-β-catenin/Snail pathway. PI3K, MEK, or GSK3β kinase and proteasome inhibition assays as well as β-Trcp and STUB1 siRNA assays were employed to determine the contribution of AKT/ERK1/2-GSK3β signaling and ubiquitin-proteasome pathway to the regulatory effects of TIPE3 on expression of β-catenin, Snail1, and Slug.ResultsWe demonstrated that TIPE3 was elevated in lung cancer tissues and cells. The expression level of TIPE3 was positively correlated with malignant clinicopathological characteristics of lung cancer patients, such as tumor size, pathologic stage, and lymph node metastasis. Knockdown of TIPE3 suppressed the proliferation and growth of NSCLC cells as well as their migration and invasion ability, whereas TIPE3 overexpression facilitated these biological processes. Mechanistic data showed that TIPE3 promoted AKT and ERK1/2 signaling, inactivated GSK3β activity, and enhanced the expression and transcriptional activity of β-catenin, Snail1, and Slug in NSCLC cells. Kinase or proteasome inhibition and β-Trcp or STUB1 knockdown assays further revealed that TIPE3 upregulated β-catenin, Snail1, and Slug via the AKT/ERK1/2-GSK3β pathway, in an ubiquitin-proteasome-dependent manner. More importantly, clinical data demonstrated that the expression level of TIPE3 was positively associated with the activation of AKT/ERK1/2-GSK3β-β-catenin/Snail pathway in lung cancer.ConclusionsOur findings indicate that upregulation of TIPE3 promotes the progression of human NSCLC considerably by activating β-catenin, Snail1, and Slug transcriptional signaling via the AKT/ERK1/2-GSK3β axis. Therefore, TIPE3 may represent a potential therapeutic target for NSCLC.

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Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression.

Publications

Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression.

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