PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma

Zhuo, Baobiao; Li, Yuan; Li, Zhengwei; Qin, Haihui; Sun, Qingzeng; Zhang, Fengfei; Shen, Yang; Shi, Yingchun; Wang, Rong

doi:10.1016/j.bbrc.2015.06.092

Cited by 70 publications

(54 citation statements)

References 37 publications

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“…HK2, hexokinase 2. attenuated after Akt overexpression, further confirming that the Akt signaling pathway is involved in the regulation of HK2 by LicA. In other cancers, such as colorectal (32), non-small cell lung cancer (33,34), pediatric osteosarcoma (35), HK2 expression was also found to be regulated by Akt activity. However, further investigation is needed to elaborate the detailed mechanism of how HK2 is mediated by Akt.…”

Section: Discussionmentioning

confidence: 58%

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway

Zhang

Wang

et al. 2017

Oncol Rep

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Licochalcone A (LicA) is a chalcone extracted from liquorice which has been used as a traditional Chinese medicine for many generations. Increased glucose consumption and glycolytic activity are important hallmarks of cancer cells, and hexokinase 2 (HK2) upregulation is a major contributor to the elevation of glycolysis. Recently, the antitumor activities of LicA have been reported in various cancers; however, its effect on tumor glycolysis in gastric cancer and the underlying mechanisms are completely unknown. In vitro, cell proliferation and clonogenic survival were substantially inhibited after LicA treatment. LicA reduced HK2 expression, and both glucose consumption and lactate production in gastric cancer cells were significantly suppressed. Mechanistic investigations revealed that multiple signaling pathways including Akt, ERK and NF‑κB were suppressed by LicA. Further studies demonstrated that the inhibition of glycolysis by LicA was mainly attributed to the blockade of the Akt signaling pathway, and the suppression of glycolysis was substantially attenuated when Akt was exogenously overexpressed. In addition to the role in the inhibition of glycolysis, reduction in HK2 was confirmed to be involved in the induction of cell apoptosis. The apoptosis induced by LicA was substantially impaired after HK2 overexpression in gastric cancer cells. The in vivo experiment showed that MKN45 xenograft growth was markedly delayed after LicA treatment and HK2 expression in LicA‑treated tissues was markedly decreased. All of these data demonstrated that blockade of the Akt/HK2 pathway was the underlying mechanism required for LicA to exert its biological activities in glycolysis inhibition and apoptosis induction.

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Section: Discussionmentioning

confidence: 58%

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway

Zhang

Wang

et al. 2017

Oncol Rep

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“…13 Second, we determined that (R,R 0 )-MNF attenuated HK2 protein levels, which is consistent with the link between the PI3K-AKT-PKM2 activation and HK2 expression. [34][35][36] HK2 plays a key role in glycolysis, 34 and elevated expression of HK2 and PKM2 are associated with an unfavorable clinical outcome and upregulated lactate production in pancreatic tumors. 37 We next employed a metabolomics approach to determine if the reduction in the expression and activation of PKM2 and HK2 affected glycolysis in PANC-1 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

Bernier

Catazaro

Singh

et al. 2017

Intl Journal of Cancer

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The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to L-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin and PI3K-AKT signaling pathways. (R,R’)-4’-methoxy-1-naphthylfenoterol ((R,R’)-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R’)-MNF’s effect on glycolysis in PANC-1 cells and tumors. Global NMR metabolomics was used to elucidate differences in the metabolome between untreated and (R,R’)-MNF-treated cells. LC/MS analysis was used to quantify intracellular concentrations of β-hydroxybutyrate, carnitine and L-lactate. Changes in target protein expression were determined by Western blot analysis. Data was also obtained from mouse PANC-1 tumor xenografts after administration of (R,R’)-MNF. Metabolomics data indicate that (R,R’)-MNF altered fatty acid metabolism, energy metabolism, and amino acid metabolism and increased intracellular concentrations of β-hydroxybutyrate and carnitine while reducing L-lactate content. The cellular content of phosphoinositide-dependent kinase-1 and hexokinase 2 was reduced consistent with diminished PI3K-AKT signaling and glucose metabolism. The presence of the GLUT8 transporter was established and found to be attenuated by (R,R’)-MNF. Mice treated with (R,R’)-MNF had significant accumulation of L-lactate in tumor tissue relative to vehicle-treated mice, together with reduced levels of the selective L-lactate transporter MCT4. Lower intratumoral levels of EGFR, pyruvate kinase M2, β-catenin, hexokinase 2 and P-glycoprotein were also observed. The data suggest that (R,R’)-MNF reduces glycolysis in PANC-1 cells and tumors through reduced expression and function at multiple controlling sites in the glycolytic pathway.

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“…Regulation of Akt on glycolysis involves HK II [90, 91], PFK2 [92], and GLUT1 [91, 93]. Akt signaling induces HK II expression [90, 91], and phosphorylates and activates PFK2 [92]. PFK2 catalyzes the production of fructose-2,6-bisphosphate, which acts as an allosteric activator of PFK1.…”

Section: Regulation Of Glycolysis In Tumorsmentioning

confidence: 99%

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

et al. 2016

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Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy.

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PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma

Cited by 70 publications

References 37 publications

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

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