Prognostic Significance of AMPK Activation and Therapeutic Effects of Metformin in Hepatocellular Carcinoma

Zheng, Liyuan; Yang, Wen; Wu, Fengyuan; Wang, Chao; Yu, Le-Xing; Tang, Liang; Qiu, Bijun; Li, Yuqiong; Guo, Linna; Wu, Meng-Chao; Feng, Gen‐Sheng; Zou, Da-jin; Wang, Hongyang

doi:10.1158/1078-0432.ccr-13-0203

Cited by 183 publications

(183 citation statements)

References 29 publications

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“…However, the mechanism underlying the anticancer effects of metformin remain to be fully elucidated Previous studies have shown that, despite the complexity of the molecular signaling mechanisms of metformin, several critical molecules and pathways have been confirmed to be involved in this regulation, including the activation of AMPK (8,18), inhibition of mammalian target of rapamycin complex-1 (19), interruption of the crosstalk between insulin and insulin-like growth factor-1 receptor (20) and reductions in the expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 (21).…”

Section: Discussionmentioning

confidence: 99%

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Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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Abstract. The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC-27 and MKN-45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma-associated oncogene (Gli)-1, Gli-2 and Gli-3 were examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP-activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli-1 were decreased by metformin treatment in the two cell lines in a dose-and time-dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli-2 and Gli-3. The small interfering RNA-induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh-induced expression of Gli-1 in HGC-27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent. IntroductionGastric cancer is one of the most common types of malignant cancer worldwide (1). In addition tosurgery, chemotherapy and radio chemotherapy, there is a demand for novel treatment approaches for gastric cancer due to its poor prognosis (2).Metformin is a widely used anti-diabetic drug, which has been reported to exhibit potential anticancer activity (3). Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4-6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7). However, the mechanism underlying the anticancer effects of metformin is complex and remains to be fully elucidated. Activation of the AMP-activated protein kinase (AMPK) pathway has been recognized as a key aspect of the anticancer effects of metformin (8).The Sonic hedgehog (Shh) signaling pathway is one of the most common signal transduction pathways in human cells (9). It is critical in normal cell differentiation and embryonic development (10). However, abnormal activation of the Shh pathway has been identified in several types of human cancer (11). Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of m...

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Section: Discussionmentioning

confidence: 99%

“…As the activation of AMPK has been considered as one important mechanism of the anticancer effects of metformin (8,18), the present study investigated whether the suppression of the Shh signaling pathway induced by metformin was AMPK-dependent. Firstly, it was demonstrated that the expression of AMPK was suppressed by siRNA specific to AMPK.…”

Section: Discussionmentioning

confidence: 99%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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“…Once activated, AMPK suppresses cell proliferation in tumor as well as non-tumor cells, through regulation of the cell cycle, apoptosis, autophagy, and inhibition of protein synthesis (20)(21)(22)(23)(24)(25). Current evidence supports the alteration of AMPK levels in various cancers, implicating AMPK as a potential target for prevention and/or treatment of cancer, specifically HCC (26)(27)(28). Several studies have also demonstrated that activation of AMPK induces apoptosis in many human cancer cells, including HCC cells (29)(30)(31).…”

Section: Introductionmentioning

confidence: 97%

“…This finding indicates that AMPK plays a critical role in HCC and that its loss can contribute to the progression of HCC. Indeed, a variety of AMPK activators show anticancer effects (27,32,33). For example, metformin, a common diabetes drug, shows anticancer effects against HCC by activation of AMPK (27,(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a variety of AMPK activators show anticancer effects (27,32,33). For example, metformin, a common diabetes drug, shows anticancer effects against HCC by activation of AMPK (27,(34)(35)(36). Similarly, a number of medicinal herb extracts exert anticancer effects through activation of AMPK-dependent cell death pathways (29,31,(37)(38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

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Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

Park

Jeong

Jeong³

et al. 2015

International Journal of Oncology

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Abstract. The Kalopanax septemlobus leaf (Thunb.) Koidz. has been used as a traditional medicine herb for the treatment of various human diseases for hundreds of years. In this study, we investigated the mechanism underlying the inhibitory effects of an ethanol extract of K. septemlobus leaf (EEKS) on proliferation of HepG2 hepatocellular carcinoma cells. For this study, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, DAPI (4,6-diamidino-2-phenylindole) staining, agarose gel electrophoresis, and flow cytometry. Measurements of the mitochondrial membrane potential (MMP), caspase activity assays and western blots were conducted to determine whether HepG2 cell death occurred by apoptosis. Treatment of HepG2 cells with EEKS concentration-dependently reduced cell survival while significantly increasing the ratio of apoptotic cells. EEKS treatment increased the levels of the death receptors (DRs), DR4 and DR5, and activated caspases, as well as promoting proteolytic degradation of poly(ADP-ribose)-polymerase associated with the downregulation of protein expression of members of the inhibitor of apoptosis protein family. Treatment with EEKS also caused truncation of Bid, translocation of pro-apoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. However, treatment of HepG2 cells with a pan-caspase inhibitor reversed EEKS-induced apoptosis and growth suppression, indicating that EEKS appears to induce apoptosis though a caspase-dependent mechanism involving both intrinsic and extrinsic apoptotic pathways. In addition, the phosphorylation level of AMP-activated protein kinase (AMPK) was elevated when cells were exposed to EEKS. A specific inhibitor for AMPK attenuated the EEKS-induced activation of caspases, and consequently prevented the EEKS-induced apoptosis and reduction in cell viability. Overall, our findings suggest that EEKS inhibits the growth of HepG2 cells by inducing AMPK-mediated caspase-dependent apoptosis, suggesting the potential therapeutic application of EEKS in the treatment or prevention of cancers.

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Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6‐independent manner

et al. 2017

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Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor‐positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5′ AMP‐activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib‐mediated HCC cell death. However, CDK4/6 inhibition by lentivirus‐mediated shRNA expression did not reproduce the effect of palbociclib‐treated cells, suggesting that the anti‐HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor‐suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.

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Prognostic Significance of AMPK Activation and Therapeutic Effects of Metformin in Hepatocellular Carcinoma

Cited by 183 publications

References 29 publications

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6‐independent manner

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