Alcohol and liver cancer

McKillop, Iain H.; Schrum, Laura W.

doi:10.1016/j.alcohol.2005.04.004

Cited by 132 publications

(132 citation statements)

References 110 publications

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“…Hepatocellular carcinomas are characterized by a switch in expression of the MAT isoenzyme from MATI͞III associated with high AdoMet and a differentiated phenotype, to MATII associated with lower AdoMet and a dedifferentiated phenotype (3). Hepatic cirrhosis is the most common precursor to development of hepatocellular carcinoma and is characterized by increased oxidative stress and decreased glutathione (2). Based on our observations, we hypothesized that down-regulation of CBS may be correlated with the spontaneous oxidative stress and liver injury associated with this pathology.…”

Section: Cbs Is Reduced In Human Livermentioning

confidence: 97%

“…Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1,2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).…”

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confidence: 99%

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S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

Prudova

Bauman

Braun

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

214

202

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The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine ␤-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by Ϸ12 kcal͞mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations. glutathione ͉ liver disease C ellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. The balance between conserving methionine via transmethylation under conditions of methionine restriction and committing it to transsulfuration under conditions of plenty is regulated at two key control points, methionine adenosyltransferase (MAT) and cystathionine ␤-synthase (CBS) (Fig. 1). Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1, 2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).Under normal conditions, coordinate regulation of methylation and antioxidant metabolism is achieved by the allosteric activation of CBS by AdoMet (Fig. 1). AdoMet is a V-type allosteric effector that increases CBS activity 2-to 3-fold (4, 5). Under conditions of plenty, methionine is directed toward cysteine synthesis via the transsulfuration pathway for use in glutathione and other cellular functions or directed toward catabolism. Cysteine is the limiting reagent in glutathione synthesis and in liver; Ϸ50% of the cysteine in glutathione is derived from methionine via the transsulf...

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Section: Cbs Is Reduced In Human Livermentioning

confidence: 97%

mentioning

confidence: 99%

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

Prudova

Bauman

Braun

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

214

202

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“…The pathogenetic mechanisms whereby alcohol intake can lead to development of cirrhosis and HCC are discussed in detail in some recent reviews (Poschl and Seitz, 2004;McKillop and Schrum, 2005;Voigt, 2005).…”

Section: Dose-effect Relationship and Threshold Of Safe Intakementioning

confidence: 99%

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

et al. 2006

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Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediatehigh prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose-effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40-60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably cofactors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1-3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC.

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“…The incidence of HCC has been increasing at an alarming rate on a global scale over the past two decades [1][2][3][4][5] . Despite a recent improvement in long-term survival rates, the prognosis of HCC is still poor.…”

Section: Introductionmentioning

confidence: 99%

The role of Med19 in the proliferation and tumorigenesis of human hepatocellular carcinoma cells

Zou

Wang

et al. 2011

Acta Pharmacol Sin

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In addition, the ability of the Med19-RNAi-Lentivirus vector-infected Hep3B cells to form tumors after inoculation into nude mice was determined. Results: Recombinant lentiviral vectors expressing small interfering RNA (siRNA) against Med19 were constructed and were found to efficiently downregulate Med19 mRNA and protein levels in HepG2 and Hep3B cells. Furthermore, the inhibition of Med19 by RNAi dramatically reduced hepatocellular carcinoma cell proliferation, induced cell-cycle arrest in the G 0 /G 1 phase, and suppressed tumor formation. Conclusion: These results provide new evidence of an important role for Med19 in the development of hepatocellular carcinomas, suggesting that lentivirus-mediated RNAi to target Med19 is a potential tool for inhibiting cancer cell proliferation and tumorigenesis.

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Alcohol and liver cancer

Cited by 132 publications

References 110 publications

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

The role of Med19 in the proliferation and tumorigenesis of human hepatocellular carcinoma cells

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