Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling

Fang, Guoxu; Zhang, Peilin; Liu, Jingfeng; Zhang, Xu; Zhu, Xiangjie; Li, Rong; Wang, Hongyang

doi:10.1016/j.canlet.2019.08.003

Cited by 63 publications

(41 citation statements)

References 39 publications

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“…Because AMPK is located at the center of multiple established tumor suppressor networks including LKB1, TSC1-TSC2 complex and p53, it is recognized to play a pivotal role in cancer progression 3 . Deficiency of AMPK pathway is known to be correlated with cancer progression in several types of cancer [33][34][35] , thus effective activation of AMPK pathway is well recognized as an efficient cancer manipulation strategy. In this study, we showed for the first time that NOD2 was an effective direct activator of AMPK pathway in HCC cells, which indicated its great potential for the manipulation of cancer.…”

Section: Discussionmentioning

confidence: 99%

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Qiu

Sun

et al. 2020

Cell Death Dis

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Nucleotide binding oligomerization domain 2 (NOD2) is a recognized innate immune sensor which can initiate potent immune response against pathogens. Many innate immune sensors have been reported to be of great importance in carcinogenesis. However, the role of NOD2 in cancer is not well understood. Here we investigated the role of NOD2 in the development of hepatocellular carcinoma (HCC). We demonstrated that NOD2 deficiency promoted hepatocarcinogenesis in N-nitrosodiethylamine (DEN)/carbon tetrachloride (CCl 4) induced HCC mice model and xenograft tumor model. In vitro investigation showed that NOD2 acted as a tumor suppressor and inhibited proliferation, colony formation and invasion of HCC cells. Clinical investigation showed that NOD2 expression was completely lost or significantly downregulated in clinical HCC tissues, and loss of NOD2 expression was significantly correlated with advanced disease stages. Further investigation showed that NOD2 exerted its anti-tumor effect through activating adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, and NOD2 significantly enhanced the sensitivity of HCC cells to sorafenib, lenvatinib and 5-FU treatment through activating AMPK pathway induced apoptosis. Moreover, we demonstrated that NOD2 activated AMPK pathway by directly binding with AMPKα-LKB1 complex, which led to autophagy-mediated apoptosis of HCC cells. Altogether, this study showed that NOD2 acted as a tumor suppressor as well as a chemotherapeutic regulator in HCC cells by directly activating AMPK pathway, which indicated a potential therapeutic strategy for HCC treatment by upregulating NOD2-AMPK signaling axis.

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Section: Discussionmentioning

confidence: 99%

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Qiu

Sun

et al. 2020

Cell Death Dis

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“…This phosphorylation increases the accessibility of the activation loop of the AMPKα subunit to phosphatases, thereby inhibiting kinase activity [94]. Importantly, Fang and coworkers [93] also demonstrated that high levels of GSK3β are an independent negative prognostic factor in HCC patients.…”

Section: Mtor Inhibitorsmentioning

confidence: 98%

“…Importantly, Ser859 Raptor phosphorylation by GSK3 was required for supporting mTORC1-directed amino acid signaling [89]. More recently, a different group reported that either pharmacological inhibition (CHIR-99021, LY2090314) or genetic downregulation of GSK3β in hepatocellular carcinoma (HCC) cells led to an activation of AMPK, thereby decreasing mTORC1 activity and glycolysis, as well as slowing proliferation of cancer cells [93]. These findings imply that GSK3β exerts a stimulatory effect on mTORC1 in HCC cells.…”

Section: Mtor Inhibitorsmentioning

confidence: 99%

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

Evangelisti

Chiarini

Paganelli

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…169 AMPK treatment options such as upregulation of HSF1, NOD2 and PEDF or inhibition of 6PGD and GSK-3β could have potential in HCC treatment. [165][166][167]170,171 Among them HSF1 also participates in the promotion of gluconeogenesis. 172 Treatments that both inhibit glycolysis and promote gluconeogenesis at the same time are expected to be promising HCC treatment solutions.…”

Section: Signaling Pathways Involved In Hcc Glucometabolic Reprogrammingmentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling

Cited by 63 publications

References 39 publications

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

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