Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading t...
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MDPI AG
2019-06-01
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| Series: | Medicina |
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| Online Access: | https://www.mdpi.com/1010-660X/55/6/296 |
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| author | Rosa M. Pascale Graziella Peitta Maria M. Simile Francesco Feo |
| author_facet | Rosa M. Pascale Graziella Peitta Maria M. Simile Francesco Feo |
| author_sort | Rosa M. Pascale |
| collection | DOAJ |
| description | Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of <i>MAT1A</i> gene under-regulation associated with up-regulation of the <i>MAT2A</i> gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of <i>c-myc, H-ras,</i> and <i>K-ras</i> expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor <i>PP2A</i> gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of <i>C/EBPα</i> and <i>UCA1</i> gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT<i>2</i>A and <i>MAT2B</i> expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC. |
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| spelling | doaj.art-3f91ecad006f4692a3bb42e0f95fe1412023-09-03T02:44:47ZengMDPI AGMedicina1010-660X2019-06-0155629610.3390/medicina55060296medicina55060296Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular CarcinomaRosa M. Pascale0Graziella Peitta1Maria M. Simile2Francesco Feo3Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, ItalyDepartment of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, ItalyDepartment of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, ItalyDepartment of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, ItalySeveral researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of <i>MAT1A</i> gene under-regulation associated with up-regulation of the <i>MAT2A</i> gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of <i>c-myc, H-ras,</i> and <i>K-ras</i> expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor <i>PP2A</i> gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of <i>C/EBPα</i> and <i>UCA1</i> gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT<i>2</i>A and <i>MAT2B</i> expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC.https://www.mdpi.com/1010-660X/55/6/296hepatocarcinogenesismethionine metabolismS-adenosylmethioninesignal transductionmechanisms of action of SAMmethyladenosyltransferases |
| spellingShingle | Rosa M. Pascale Graziella Peitta Maria M. Simile Francesco Feo Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma Medicina hepatocarcinogenesis methionine metabolism S-adenosylmethionine signal transduction mechanisms of action of SAM methyladenosyltransferases |
| title | Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma |
| title_full | Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma |
| title_fullStr | Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma |
| title_full_unstemmed | Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma |
| title_short | Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma |
| title_sort | alterations of methionine metabolism as potential targets for the prevention and therapy of hepatocellular carcinoma |
| topic | hepatocarcinogenesis methionine metabolism S-adenosylmethionine signal transduction mechanisms of action of SAM methyladenosyltransferases |
| url | https://www.mdpi.com/1010-660X/55/6/296 |
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