S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x<sub>S</sub>

Yang, Heping; Sadda, Mamatha; Li, Mei; Zeng, Ying; Chen, Lixin; Bae, Wanjun; Ou, Xiaopeng; Runnegar, Maria T. C.; Mato, José M.; Lu, Shelly C.

doi:10.1002/hep.20274

Cited by 77 publications

(81 citation statements)

References 37 publications

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“…oncogenic mechanisms such as AKT to promote apoptosis and attenuate growth progression in liver and colon cancers . More importantly, these compounds are antiapoptotic in normal hepatocytes (Ansorena et al, 2002;Yang et al, 2004) and have no toxic effects toward normal colon epithelial cells (Li et al, 2012). Because SAMe and MTA are naturally occurring compounds found in our bodies, it makes them the ideal candidates for preventing and/or treating cancers with aberrant Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

Peng

Yang

et al. 2014

Mol Pharmacol

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S-Adenosylmethionine (SAMe), the principal methyl donor that is available as a nutritional supplement, and its metabolite methylthioadenosine (MTA) exert chemopreventive properties against liver and colon cancer in experimental models. Both agents reduced b-catenin expression on immunohistochemistry in a murine colitis-associated colon cancer model. In this study, we examined the molecular mechanisms involved. SAMe or MTA treatment in the colitis-associated cancer model lowered total b-catenin protein levels by 47 and 78%, respectively. In an orthotopic liver cancer model, increasing SAMe levels by overexpressing methionine adenosyltransferase 1A also reduced total b-catenin levels by 68%. In both cases, lower cyclin D1 and c-Myc expression correlated with lower b-catenin levels. In liver (HepG2) and colon (SW480, HCT116) cancer cells with constitutively active b-catenin signaling, SAMe and MTA treatment inhibited b-catenin activity by excluding it from the nuclear compartment. However, in liver (Huh-7) and colon (RKO) cancer cells expressing wild-type Wnt/b-catenin, SAMe and MTA accelerated b-catenin degradation by a glycogen synthase kinase 3-b-dependent mechanism. Both agents lowered protein kinase B activity, but this was not mediated by inhibiting phosphoinositide 3-kinase. Instead, both agents increased the activity of protein phosphatase 2A, which inactivates protein kinase B. The effect of MTA on lowering b-catenin is direct and not mediated by its conversion to SAMe, as blocking this conversion had no influence. In conclusion, SAMe and MTA inhibit Wnt/b-catenin signaling in colon and liver cancer cells regardless of whether this pathway is aberrantly induced, making them ideal candidates for chemoprevention and/or chemotherapy in these cancers.

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Section: Discussionmentioning

confidence: 99%

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

Peng

Yang

et al. 2014

Mol Pharmacol

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“…Lentivirus vector encoding antisense targeting HIV envelope sequence has been used for HIV treatment in clinical trials with no obvious side effects [26,27] . Most recently, lentivirus vector containing beta-globin gene has been approved in phaseⅠ/Ⅱ clinical trials for human betathalassemia and sickle cell anemia gene therapy [28] . The MAT2B's expression is very important because it not only can provide a proliferative advantage in hepatoma cells but can also decrease intracellular SAMe content.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

Wang¹,

Liu²,

Liu³

et al. 2008

WJG

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AIM:To investigate the effects of lentivirus vector mediated short hairpin RNA interference targeting methionine adenosyltransferase 2β gene (LV-shMAT2B) on hepatocellular carcinoma (HCC) cells. METHODS:We constructed four plasmids of RNA interference targeting the MAT2B gene. After LVshMAT2B was transfected with L-02 cells and two kinds of HCC cells, cell viability and proliferation were measured with MTT and [3H]thymidine assays respectively. Flow cytometry was used to assess cell apoptosis. The level of S-adenosyl methionine (SAMe) in HepG2 cells was evaluated. The expressions of cyclin D1, cyclin D2, bcl-x L and bcl-x S were detected with western blot. RESULTS: We constructed LV-shMAT2B successfully. LV-shMAT2B was safe for human normal liver cells. LVshMAT2B caused dramatic reduction in proliferation c o m p a re d w i t h controls in HCC cel ls B el-7402 (P = 0.054) and HepG2 (P = 0.031). Flow cytometry analysis showed that cell apoptosis caused by LVshMAT2B was greater in HCC cells Bel-7402 and HepG2 than in control induced by scrambled siRNA (P = 0.047), but apoptosis rates in L-02 induced by LV-shMAT2B and scrambled siRNA respectively had no significant difference. Moreover, LV-shMAT2B significantly suppressed expression of MAT2B leading to growthinhibition effect on HCC cells by down-regulating cyclin D1. Apoptosis induced by LV-shMAT2B was involved in down-regulating bcl-x L and up-regulating bcl-x S . CONCLUSION: LV-shMAT2B can induce cell apoptosis and growth-inhibition in HCC cells. MAT2B may be a therapy target in HCC in the future.

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“…34 We have identified two mechanisms of SAMe's and MTA's differential effect on apoptosis in normal hepatocytes and liver cancer cells thus far. 14,41 Using microarray, we found SAMe treatment induced Bcl-x expression. Bcl-x is alternatively spliced to produce two distinct mRNAs and proteins, Bcl-x L and Bcl-x S .…”

Section: Same Regulation Of Hepatocyte Apoptosismentioning

confidence: 96%

“…4,42,47 Whereas SAMe protects normal hepatocytes, it induces apoptosis in liver cancer cells. 39,41 This makes SAMe an attractive candidate for chemoprevention of liver cancer. Interestingly, SAMe's effect on growth, apoptosis, and tumor necrosis factor alpha expression 48 can be mimicked by MTA.…”

Section: Mechanisms Of Same Action: Role Of Mtamentioning

confidence: 99%

Role of S-adenosyl-L-methionine in liver health and injury

2007

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S-Adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte growth, death, and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of all forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and hepatocellular carcinoma. However, impaired SAMe metabolism, which occurs in patients with mutations of glycine N-methyltransferase (GNMT), can also lead to liver injury. This suggest that hepatic SAMe level needs to be maintained within a certain range, and deficiency or excess can both lead to abnormality. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also show it is effective in patients with cholestatic liver diseases. Recent data show that exogenous SAMe can regulate hepatocyte growth and death, independent of its role as a methyl donor. This raises the question of its mechanism of action when used pharmacologically. Indeed, many of its actions can be recapitulated by methylthioadenosine (MTA), a by-product of SAMe that is not a methyl donor. A better understanding of why liver injury occurs when SAMe homeostasis is perturbed and mechanisms of action of pharmacologic doses of SAMe are essential in defining which patients will benefit from its use. (HEPATOLOGY 2007;45: 1306-1312.)

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S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x_S

Cited by 77 publications

References 37 publications

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

Role of S-adenosyl-L-methionine in liver health and injury

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S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-xS

Cited by 77 publications

References 37 publications

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

Role of S-adenosyl-L-methionine in liver health and injury

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S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x_S