Metformin Prevents Liver Tumorigenesis by Inhibiting Pathways Driving Hepatic Lipogenesis

Bhalla, Kavita; Hwang, Bor Jang; Dewi, Ruby E.; Twaddel, William; Goloubeva, Olga; Wong, Kwok-Kin; Saxena, Neeraj K.; Biswal, Shyam; Girnun, Geoffrey D.

doi:10.1158/1940-6207.capr-11-0228

Cited by 138 publications

(134 citation statements)

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(60 reference statements)

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“…Metabolic disorders have been identified as a hallmark of cancer (Hanahan and Weinberg, 2011). Activation of de novo lipogenesis is found in many types of malignancy, including HCC (Bhalla et al ., 2012; Jacobs et al ., 2012; Liu et al ., 2016; Rysman et al ., 2010). In cancer cells, unrestricted lipogenesis is essential for the continued supply of lipids and lipid precursors to maintain membrane production, synthesis of signal transducers, and post‐translational modification of proteins (Menendez and Lupu, 2007; Swinnen et al ., 2006).…”

Section: Introductionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.

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Section: Introductionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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“…Potential utility of metformin for prevention of hepatocellular carcinoma in high risk populations should be regarded as a high priority for investigation, because of favorable pharmacokinetics for this organ, encouraging predictions from laboratory models, and provocative results from cohort studies, such as a recent report from France that documented a substantial (>50%) decline in hepatitis C-associated hepatocellular carcinoma among metformin exposed subjects (20). Both cellautonomous actions and systemic effects of metformin, particularly on insulin (21), deserve scrutiny in efforts to uncover the mechanism(s) underlying the cancer prevention activity of this agent observed in models such as the one reported by Bhalla et al (2).…”

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confidence: 96%

“…There is tantalizing evidence that this widely used, well-tolerated biguanide molecule may have applications in cancer prevention or treatment (1). In this issue of the journal, Bhalla and colleagues present interesting experimental evidence for an action of metformin in inhibiting the development of chemically induced hepatocellular carcinoma in mice (2), yet many important questions remain unanswered.…”

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confidence: 99%

“…Many experimental studies demonstrate cancer treatment or prevention activity of metformin attributable to direct actions of the drug on target cells that are independent of (8), as emphasized in the study by Bhalla and colleagues (2). Although this inhibition is a consequence of 5 0 AMP-activated protein kinase (AMPK) activation due to metformin-induced energy stress in some models (9), this was not the case in the data reported by Bhalla and colleagues (2).…”

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confidence: 99%

“…Although this inhibition is a consequence of 5 0 AMP-activated protein kinase (AMPK) activation due to metformin-induced energy stress in some models (9), this was not the case in the data reported by Bhalla and colleagues (2). Another direct action of metformin that arises as a consequence of AMPK activation is the inhibition of protein translation as a consequence of inhibition of mTOR (10).…”

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Metformin and Hepatic Carcinogenesis

Pollak

González-Angulo

2012

Cancer Prevention Research

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Retrospective, hypothesis-generating population studies suggest that diabetics treated with metformin have a substantially reduced risk of several cancers, including hepatoma, relative to diabetics on other therapies. In this issue of the journal (beginning on page 544), Bhalla and colleagues contribute to the growing literature on metformin effects in experimental carcinogenesis models, showing reduced carcinogen-induced hepatoma in mice. The clinical need to develop novel prevention strategies for hepatoma is obvious, given an increasing prevalence and poor prognosis. The clues that metformin or related biguanides may have utility in this area justify accelerated laboratory research, as more data concerning mechanism, pharmacokinetics, and predictors of efficacy will help to optimize the design of clinical trials. Cancer Prev Res; 5(4); 500-2. Ó2012 AACR.The literature on metformin and cancer has grown rapidly in the past few years. There is tantalizing evidence that this widely used, well-tolerated biguanide molecule may have applications in cancer prevention or treatment (1). In this issue of the journal, Bhalla and colleagues present interesting experimental evidence for an action of metformin in inhibiting the development of chemically induced hepatocellular carcinoma in mice (2), yet many important questions remain unanswered.Several proposed mechanisms of action of metformin may underlie its activity as a cancer preventive agent. Some (but not all) of these mechanisms may overlap with the actions that are responsible for the utility of the compound in the treatment of type II diabetes. It is now thought that the pleiotropic effects of metformin originate with the primary actions of the drug on the mitochondria (3), where it inhibits oxidative phosphorylation (at respiratory complex I) in a manner that has not yet been described in detail. Sequelae to this inhibition occur at the local mitochondrial level, at the cellular level, and at the level of the whole organism. The best known local consequence is the decline of mitochondrial ATP production (1), but there is also recent evidence for altered redox status, a decrease in reactive oxygen species (ROS) production, and a decrease in mutations attributable to ROS (4). At the cellular level, the reduction in ATP production by oxidative phosphorylation leads to a degree of energy stress. This stress can have different effects depending on the cellular context. Some cells have the ability to sense and respond to the stress by decreasing energy-consuming processes such as lipid synthesis, protein synthesis, and proliferation (1, 3). This decrease results in a new steady state characterized by reduced ATP production, reduced ATP consumption, and an energetically "sleepy" phenotype, which may tend to slow carcinogenesis and may also be cytostatic for a subset of established cancers. Another compensation involves increasing glycolysis to help correct the ATP deficit. This process may seem paradoxical at first, as it represents a situation of increased glu...

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Arachidonic acid suppresses hepatic cell growth through ROS‐mediated activation of transglutaminase

Qin

Cai

2018

FEBS Open Bio

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We previously reported a profound augmentation in the hepatic levels of a pro‐inflammatory precursor, arachidonic acid ( AA ), during liver tumorigenesis. Here, we report a critical role of the induced reactive oxygen species ( ROS )‐mediated cellular activation of a protein cross‐linking enzyme, transglutaminase 2 ( TG 2), in liver injury by AA . In cultures of hepatic cells, AA dose‐dependently suppressed cell growth, which accompanied the induced nuclear accumulation of TG 2, as demonstrated in EGFP ‐tagged, TG 2‐overexpressing hepatic cells. A chemical inhibitor/sh RNA that acts against TG 2 prevented AA ‐mediated cell growth suppression. In addition, AA provoked significant production of ROS , and antioxidants blocked AA ‐induced activation of nuclear TG 2 and hepatic cell growth suppression. We propose that AA ‐mediated oxidative stress and TG 2 transamidase activity might contribute to chronic liver injury and inflammation and thereby serve as potential therapeutic targets for the chemoprevention of hepatocellular carcinoma.

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Metformin Prevents Liver Tumorigenesis by Inhibiting Pathways Driving Hepatic Lipogenesis

Cited by 138 publications

References 50 publications

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Metformin and Hepatic Carcinogenesis

Arachidonic acid suppresses hepatic cell growth through ROS‐mediated activation of transglutaminase

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