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TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1? axis and indicates prognosis in pancreatic cancer.

ABSTRACT: Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/?-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a ?-catenin transcriptional partner, plays a vital role in the Wnt/?-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1?). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing 18FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.

SUBMITTER: Xiang J

PROVIDER: S-EPMC5833500 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer.

Xiang Jinfeng J Hu Qiangsheng Q Qin Yi Y Ji Shunrong S Xu Wenyan W Liu Wensheng W Shi Si S Liang Chen C Liu Jiang J Meng Qingcai Q Liang Dingkong D Ni Quanxing Q Xu Jin J Zhang Bo B Yu Xianjun X

Cell death & disease 20180223 3

Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathwa ...[more]

PMID: 29476053

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Project description:ObjectivesReprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown.Materials and methodsLoss-of-function and gain-of-function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real-time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms.ResultsPRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss-of-function and gain-of-function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia-inducible factor 1α (HIF-1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF-1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1α.ConclusionsOur study identified that PRKAR2B-HIF-1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.

Project description:A previously validated anti-rheumatic compound α-mangostin (MAN) shows significant metabolism regulatory effects. The current study aimed to clarify whether this property contributed to its inhibition on synovial angiogenesis. Male wistar rats with adjuvant-induced arthritis (AIA) were orally treated by MAN for 32 days. Afterwards, biochemical parameters and cytokines in plasma were determined by corresponding kits, and glycometabolism-related metabolites were further accurately quantified by LC-MS method. Anti-angiogenic effects of MAN were preliminarily assessed by joints based-immunohistochemical examination and matrigel plug assay. Obtained results were then validated by experiments in vitro. AIA-caused increase in circulating transforming growth factor beta, interleukin 6, hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in blood and local HIF-1α/VEGF expression in joints was abrogated by MAN treatment, and pannus formation within matrigel plugs implanted in AIA rats was inhibited too. Scratch and transwell assays revealed the inhibitory effects of MAN on human umbilical vein endothelial cells (HUVECs) migration. Furthermore, MAN inhibited tubule formation capability of HUVECs and growth potential of rat arterial ring-derived endothelial cells in vitro. Meanwhile, MAN eased oxidative stress, and altered glucose metabolism in vivo. Glycolysis-related metabolites including glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglyceric acid and phosphoenolpyruvic acid in AIA rats were decreased by MAN, while the impaired pyruvate-synthesizing capability of lactate dehydrogenase (LDH) was recovered. Consistently, MAN restored lipopolysaccharide-elicited changes on levels of glucose and LDH in HUVECs culture system, and exerted similar effects with LDH inhibitor stiripentol on glycometabolism and VEGF production as well as tubule formation capability of HUVECs. These evidences show that MAN treatment inhibited aerobic glycolysis in AIA rats, which consequently eased inflammation-related hypoxia, and hampered pathological neovascularization.

Project description:Background and Objective: Glucose fluctuation (GF) has been reported to induce renal injury and diabetic nephropathy (DN). However, the mechanism still remains ambiguous. Mitochondrial energy metabolism, especially aerobic glycolysis, has been a hotspot of DN research for decades. The activation of HIF-1α/miR210/ISCU/FeS axis has provided a new explanation for aerobic glycolysis. Our previous studies indicated quercetin as a potential therapeutic drug for DN. This study aims to evaluate levels of aerobic glycolysis and repressive effect of quercetin via HIF-1α/miR210/ISCU/FeS axis in a cell model of GF. Methods: The mouse glomerular mesangial cells (MCs) were exposed in high or oscillating glucose with or without quercetin treatment. Cell viability was measured by CCK8 assay. Aerobic glycolysis flux was evaluated by lactate acid, pH activity of PFK. Apoptosis level was confirmed by Annexin V-APC/7-AAD double staining and activity of caspase-3. TNF-α and IL-1β were used to evaluate inflammation levels. Results: GF deteriorated inflammation damage and apoptosis injury in MCs, while quercetin could alleviate this GF-triggered cytotoxicity. GF intensified aerobic glycolysis in MCs and quercetin could inhibit this intensification in a dose-dependent manner. Quercetin prevented activities of two FeS-dependent metabolic enzymes, aconitase, and complex I, under GF injury in MCs. The mRNA expression and protein contents of HIF-1α were increased after GF exposure, and these could be alleviated by quercetin treatment. Knockdown of ISCU by siRNA and Up-regulating of miR-210 by mimic could weaken the effects of quercetin that maintained protein levels of ISCU1/2, improved cell viability, relieved inflammation injury, decreased apoptosis, and reduced aerobic glycolysis switch in MCs. Conclusion: Quercetin antagonizes GF-induced renal injury by suppressing aerobic glycolysis via HIF-1α/miR-210/ISCU/FeS pathway in MCs cell model. Our findings contribute to a new insight into understanding the mechanism of GF-induced renal injury and protective effects of quercetin.

Dataset Information

TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1? axis and indicates prognosis in pancreatic cancer.

Publications

TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer.

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