Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma

Liu, Ruiqi; Li, Yuejin; Tian, Lantian; Shi, Huawen; Wang, Jiabei; Liang, Yingjian; Sun, Bei; Wang, Shuangjia; Zhou, Meng; Wu, Li; Nie, Jianhua; Lin, Binlin; Tang, Shuli; Zhang, Yanqiao; Wang, Guangyu; Zhang, Chunhui; Han, Jiguang; Xu, Benjie; Liu, Lianxin; Gong, Ke; Zheng, Tongsen

doi:10.1016/j.canlet.2018.11.030

Cited by 92 publications

(76 citation statements)

References 31 publications

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“…C-Myc is reported to overexpressed in HCC, and can promote the Warburg effect by increasing the expression of glycolytic related markers, such as GLUT1, LDH and PKM2 [66][67][68][69]. Conversely, c-Myc can also be regulated by PKM2 in the nucleus, for PKM2 can translocate into nucleus and act as a coactivator of β-catenin to induce c-Myc expression, leading to the expression of c-Myc targeted genes [30,67]. In addition, high levels of c-Myc activity will enhance the PKM2/PKM1 ratios [49,70].…”

Section: Discussionmentioning

confidence: 99%

“…The lactate assay kit was obtained from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Glucose uptake levels were calculated using a glucose detection kit from Rongsheng Biotechnology (Shanghai, China), and the values were normalized to the protein concentrations of the cell lysates [10,30]. The triglyceride (TG), total cholesterol (TCHO) lowdensity lipoprotein cholesterol (LDL-C) and the highdensity lipoprotein cholesterol (HDL-C) assay kits were all purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China).…”

Section: Biomedical Analysismentioning

confidence: 99%

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Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

158

127

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

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Section: Discussionmentioning

confidence: 99%

Section: Biomedical Analysismentioning

confidence: 99%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

158

127

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“…Accumulating studies have enhanced our understanding of the molecular mechanisms underlying the metabolic reprogramming associated with HCC progression; however, the role of aerobic glycolysis in cancer cell growth and metastasis remains unclear [24,25]. We therefore explored the effect of TMEM147 on HCC progression and revealed the mechanism underlying the EGFR/MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

TMEM147 promotes hepatocellular carcinoma progress by inducing EGFR/MAPK activity

Sun

Song

et al. 2020

Preprint

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Backgroud: Hepatocellular carcinoma (HCC) is characterized by rapid early proliferation and distant metastasis and is extremely difficult to treat. Aerobic glycolysis is a hallmark of abnormal glucose metabolism in cancer cells as has been shown to be associated with tumor proliferation and metastasis; however, the mechanisms underlying aerobic glycolysis remain unclear.Methods: Immunohistochemistry (IHC) and qRT-PCR was performed to investigate the association between TMEM147 expression and the clinicopathological characteristics and prognosis of patients with HCC. Loss-and gain-of function assays were performed to investigate the role of TMEM147 in proliferation, metastasis and glycolysis in vitro and vivo. Bioinformatic analysis and rescue assay were used to demonstrated the TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane.Results: we identified TMEM147 as a protein that was highly expressed and associated with poor survival in patients with HCC. Both gain-and loss-of-function studies revealed that TMEM147 acted as a key oncoprotein by promoting HCC growth, metastasis, and glycolysis via the EGFR/ MAPK signaling pathway. Mechanistically, TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane, thus increasing the stability of EGFR and prolonging activation of the downstream MAPK pathway. Conclusion:Collectively, these results demonstrated the role and functional mechanism of TMEM147 in HCC, and indicated that TMEM147 may represent a prognostic biomarker and potential therapeutic target for HCC. BackgroundHepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide [1].Although improvements in many therapeutic strategies, including surgical resection, liver transplantation, and radiofrequency ablation, have improved the 5-year survival rate of HCC patients, its prognosis remains unsatisfactory [2]. Survival is associated with the use of targeted treatments, such as the tyrosine kinase inhibitor sorafenib, in patients with advanced stage cancer with vascular invasion and distant metastasis [3,4]. Clarifying the biological processes and molecular mechanisms

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“…b-catenin and c-Myc are proved to be the key proteins in GSHdependent stemness maintenance and sorafenib resistance [61,62]. In contrast, decreased glutaminolysis mediated by glutamine synthetase (GS) contributes to enhanced sensitivity to sorafenib in HCC [63].…”

Section: Sorafenib-induced Oxidative Stress and Reactive Oxygen Specimentioning

confidence: 99%

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

et al. 2020

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A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

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Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma

Cited by 92 publications

References 31 publications

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

TMEM147 promotes hepatocellular carcinoma progress by inducing EGFR/MAPK activity

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

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