Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma

Abstract

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 MAT1A gene under-regulation associated with up-regulation of the MAT2A 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 c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 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 MAT2A and MAT2B 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.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice

“…GNMT is the most abundant hepatic methyltransferase that acts as a sink by transferring methyl groups from SAM to glycine to reduce SAM levels in order to regulate methionine consumption and SAM levels 7 . Interestingly, repression of Mat1a with the induction of Mat2a, which is usually only expressed during liver development, is characteristic of NAFLD and aggressive hepatocellular carcinoma progression [68][69][70][71][72] .…”

Proposed Neuroimmune Roles of Dimethyl Fumarate, Bupropion, S-Adenosylmethionine, and Vitamin D3 in Affording a Chronically Ill Patient Sustained Relief from Inflammation and Major Depression

“…Necroptosis of cells increase proinflammatory cytokines that fuel inflammation and cause bystander tissue damage in addition to summoning neutrophils and macrophages to the site of inflammation. In addition, the dying cells help raise levels of matrix metallo proteases that encourage scar formation, and protein fibers, which form scars in damaged tissues [ 83 , 127 , 128 , 129 , 130 , 131 ].…”

“…Upon introduction into the body through diet, or via synthesis from 7-dehydrocholesterol in skin keratinocytes, pre-vitamin D 3 is carried to the liver by serum albumins, wherein hydroxylation at carbon-25 (C25) with cytochrome P450-2R1, converts pre-vit-D3 to calcidiol, 25(OH)D 3 . Thereafter, calcidiol is carried by serum α-globulins into the kidneys where it is converted to calcitriol (1,25(OH) 2 D 3 ), by cytochrome P450-27B1, see Figure 7 [ 131 , 132 , 133 , 134 , 135 , 142 , 143 , 144 , 145 ].…”

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

“…Instead of being converted into cysteine, homocysteine can be irreversibly remethylated into methionine, but high SAM levels inhibit this reaction, therefore stimulating cysteine synthesis and GSH production [41]. Hence, SAM increases ROS detoxification through glutathione metabolism modulation [42,43].…”