Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth

Wang, Lei; Xiong, Hua; Wu, Fengxia; Zhang, Yingjie; Wang, Ji; Zhao, Liyan; Guo, Xiaolan; Chang, Li Ju; Zhang, Yong; You, M. James; Koochekpour, Shahriar; Saleem, Mohammad; Huang, Haojie; Lü, Junxuan; Deng, Yibin

doi:10.1016/j.celrep.2014.07.053

Cited by 234 publications

(238 citation statements)

References 43 publications

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“…PFKFB3 is not a rate-limiting glycolytic enzyme; instead it catalyzes the conversion of fructose-6-phosphate to fructose-2,6-bisphosphate, an allosteric activator of PFK1 and a potent stimulator of glycolysis (30)(31)(32). PFK1 and HK2, rate-limiting enzymes in the glycolytic pathway (33,34), were also significantly up-regulated in TGF-b1-induced lung myo-Fbs ( Figures 2B and 2C). These data suggest that the augmented glycolytic program in lung myo-Fbs is caused by increased expression of key enzymes that catalyze this process.…”

Section: Key Glycolytic Enzymes Are Up-regulated In Lung Myo-fbsmentioning

confidence: 79%

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

Xie

Tan

Banerjee

et al. 2015

Am J Respir Crit Care Med

386

381

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Rationale: Dysregulation of cellular metabolism has been shown to participate in several pathologic processes. However, the role of metabolic reprogramming is not well appreciated in the pathogenesis of organ fibrosis.Objectives: To determine if glycolytic reprogramming participates in the pathogenesis of lung fibrosis and assess the therapeutic potential of glycolytic inhibition in treating lung fibrosis.Methods: A cell metabolism assay was performed to determine glycolytic flux and mitochondrial respiration. Lactate levels were measured to assess glycolysis in fibroblasts and lungs. Glycolytic inhibition by genetic and pharmacologic approaches was used to demonstrate the critical role of glycolysis in lung fibrosis.Measurements and Main Results: Augmentation of glycolysis is an early and sustained event during myofibroblast differentiation, which is dependent on the increased expression of critical glycolytic enzymes, in particular, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3). Augmented glycolysis contributes to the stabilization of hypoxia-inducible factor 1-a, a master regulator of glycolytic enzymes implicated in organ fibrosis, by increasing cellular levels of tricarboxylic acid cycle intermediate succinate in lung myofibroblasts. Inhibition of glycolysis by the PFKFB3 inhibitor 3PO or genomic disruption of the PFKFB3 gene blunted the differentiation of lung fibroblasts into myofibroblasts, and attenuated profibrotic phenotypes in myofibroblasts isolated from the lungs of patients with idiopathic pulmonary fibrosis. Inhibition of glycolysis by 3PO demonstrates therapeutic benefit in bleomycin-induced and transforming growth factor-b1-induced lung fibrosis in mice.Conclusions: Our data support the novel concept of glycolytic reprogramming in the pathogenesis of lung fibrosis and provide proof-of-concept that targeting this pathway may be efficacious in treating fibrotic disorders, such as idiopathic pulmonary fibrosis.

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Section: Key Glycolytic Enzymes Are Up-regulated In Lung Myo-fbsmentioning

confidence: 79%

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

Xie

Tan

Banerjee

et al. 2015

Am J Respir Crit Care Med

386

381

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“…Several tumorigenic pathways enhance HK2 transcription, including p53 and p53 mutants in hepatoma cells (20); Pten and p53 deficiency, through activation of the AKT-mTORC1-4EBP1 axis and inhibition of miRNA143, respectively, in prostate cancer (41); and peroxisome proliferator-activated receptor-γ (PPARγ) in liver (42). These suggest that ΔNp63 could have a role in regulation of HK2 transcription downstream of AKT in cooperation with PPARγ, contributing to metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

p63 supports aerobic respiration through hexokinase II

Viticchiè

Agostini

Lena

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Short p63 isoform, ΔNp63, is crucial for epidermis formation, and it plays a pivotal role in controlling the turnover of basal keratinocytes by regulating the expression of a subset of genes involved in cell cycle and cell adhesion programs. The glycolytic enzyme hexokinase 2 (HK2) represents the first step of glucose utilization in cells. The family of HKs has four isoforms that differ mainly in their tissue and subcellular distribution. The preferential mitochondrial localization of HK2 at voltage-dependent anion channels provides access to ATP generated by oxidative phosphorylation and generates an ADP/ATP recycling mechanism to maintain high respiration rates and low electron leak. Here, we report that ΔNp63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show ΔNp63-dependent regulation of HK2 expression, and we use ChIP, validated by p63-Chip sequencing genomewide profiling analysis, and luciferase assays to demonstrate the presence of one p63-specific responsive element within the 15th intronic region of the HK2 gene, providing evidence of a direct interaction. Our data support the notion of ΔNp63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The ΔNp63-HK2 axis is also present in epithelial cancer cells, suggesting that ΔNp63 could participate in cancer metabolic reprogramming.p63 | HK2 | keratinocytes | oxidative metabolism | mitochondria

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“…Various studies have demonstrated that mutation of the p53 gene has a significant role in tumor development (12)(13)(14)(15)(16)(17). When DNA is damaged by physical and/or chemical factors, p53 gene transcription is increased and wild-type p53 protein is concentrated, which results in arrest of the cell cycle at G1/S phase and apoptosis of cells with cancerous characteristics (18).…”

Section: Introductionmentioning

confidence: 99%

Expression of mutant p53 in oral squamous cell carcinoma is correlated with the effectiveness of intra-arterial chemotherapy

Zhang

2015

Oncology Letters

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Abstract. The aim of the present study was to evaluate the correlation between the positive expression rate of mutant p53 and the clinical characteristics of patients with oral squamous cell carcinoma (OSCC), as well as the effectiveness of intra-arterial chemotherapy. Expression of mutant p53 in tumor tissues was determined by immunohistochemical analysis of 51 OSCC patients, prior to and following intra-arterial chemotherapy. Prior to intra-arterial chemotherapy, mutant p53 positive rates in patients with higher pathological grades were significantly higher than those of the patients with lower pathological grades. The mutant p53 positive rate in patients with lymph node metastasis was 73% (19/26), which was significantly higher than that of the patients without lymph node metastasis (20%, 5/25). Mutant p53 was expressed in 17% (3/18) of clinical phase II patients, while 64% (21/33) of clinical phase III and IV patients exhibited positive expression of mutant p53 (P<0.05). The mutant p53 positive rate in chemotherapy non-responsive patients was 69% (11/16), which was significantly higher than that in the chemotherapy-responsive patients (37%, 13/35). Mutant p53 positive rates were not significantly correlated with age, gender or the location of the tumor. The mutant p53 positive rate prior to chemotherapy was 47% (24/51), and decreased to 18% (9/51) following chemotherapy. Expression of mutant p53 was decreased in all 13 (100%) chemotherapy-responsive patients, while only 5 (45%) chemotherapy non-responsive patients exhibited reduced expression levels of mutant p53 (P<0.05). In conclusion, mutant p53 has a significant role in the differentiation, development and treatment guidance of OSCC. Intra-arterial chemotherapy with 5-fluorourcil and carboplatin potentially exerts a therapeutic effect by reducing the expression of mutant p53.

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Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth

Cited by 234 publications

References 43 publications

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

p63 supports aerobic respiration through hexokinase II

Expression of mutant p53 in oral squamous cell carcinoma is correlated with the effectiveness of intra-arterial chemotherapy

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