s-adenosylhomocysteine and Adenocarcinoma

This study reports the influence of colorectal neoplasia on methylation intermediates and folate concentrations in human colonic mucosa, as well as systemic measures of folate status, to examine biomarkers and possible mechanisms of folate-related carcinogenesis.. A total of 47 patients were selected from those previously diagnosed with adenocarcinoma of the colorectum undergoing surgery. For each individual, we obtained a biopsy of the adenocarcinoma and a biopsy of normal appearing mucosa, to perform an intra-individual comparison.. The 'methylation' ratio (S-adenosylmethionine/S-adenosylhomocysteine (SAH)) was lower in pathological tissue vs normal mucosa (P=0.08), mainly due to a much higher SAH concentration (P<0.005). Colonic folate concentration was significantly diminished in malignant tissue (P<0.0001). Plasma homocysteine concentration was within the normal to high range, and folate and vitamin B12 plasma concentrations were within the low to normal range as compared with normative values.. Our results contribute to the hypothesis that altered DNA methylation and methyl metabolism is associated with colorectal neoplasia.

Topics: Adenocarcinoma; Aged; Colon; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Homocysteine; Humans; Intestinal Mucosa; Male; Nutritional Status; S-Adenosylhomocysteine; S-Adenosylmethionine

In this study we investigated the signalling requirements for TNF-induced cytotoxicity modulated by the methyltransferase inhibitor S-adenosyl-L-homocysteine (AdoHcy) using the TNF-sensitive human breast carcinoma MCF7 cells and its established TNF-resistant clones (R-A1 and clone 1001). Our data indicate that inhibition of methylation reactions by adenosine plus homocysteine, which are known to condense within cells to AdoHcy, markedly potentiated TNF-induced cytotoxicity in MCF7 cells and rendered related TNF-resistant variants, TNF-sensitive by a mechanism independent from the ceramide pathway. We demonstrated that the dominant-negative derivative of FADD (FADD-DN) blocked methylation inhibition/TNF-induced cell death. Moreover, TNF-mediated cytotoxicity modulated by AdoHcy was blocked by the ICE-inhibiting peptide z-VAD-fmk, suggesting that an ICE-like protease is required for the methylation inhibition/TNF-inducible death pathway. In conclusion, these results suggest that the methyltransferase inhibitor AdoHcy potentiates TNF-induced cytotoxicity in MCF7 cells and renders TNF-resistant MCF7 clones, TNF-sensitive via the ceramide independent pathway and that FADD and the ICE-like protease are likely necessary components in transducing methylation inhibition/TNF signals for cell death.

Topics: Adenocarcinoma; Amino Acid Chloromethyl Ketones; Apoptosis; Arabidopsis Proteins; Breast Neoplasms; Caspase Inhibitors; Ceramides; Cysteine Proteinase Inhibitors; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Drug Resistance; Fatty Acid Desaturases; Female; Humans; Recombinant Fusion Proteins; S-Adenosylhomocysteine; Tumor Necrosis Factor-alpha

The processing pathway of G-proteins and Ras family proteins includes the isoprenylation of the cysteine residue, followed by proteolysis of three terminal residues and alpha-carboxyl methyl esterification of the cysteine residue. Farnesylcysteine methyltransferase (FCMT) activity is responsible for the methylation reaction which play a role in the membrane attachment of a variety of cellular proteins. Four kinds of Ras protein (c-Ha-ras, c-N-Ras, c-Ki-Ras, pan-Ras) expression were detected in adenocarcinoma of human tissue by immunohistochemical method, and hematoxylin and eosin staining. The level of Ras protein in human stomach tumor tissues was much higher than in normal and peritumoral regions of the same biopsy samples. The FCMT activities of each cellular fractions were high in mitochondrial fraction followed by microsomal fraction, whole homogenate and cytosolic fraction. The inhibitory effect on FCMT activity on stomach tumor tissue was determined after treatment with 0.25 microM of S-adenosyl-L-homocysteine. S-adenosyl-L-homocysteine inhibited FCMT activity from 11.2% to 30.5%. These results suggested that FCMT might be involved in Ras proteins activity.

Topics: Adenocarcinoma; Adult; Aged; Cysteine; Enzyme Activation; Gene Expression; Humans; Immunohistochemistry; Middle Aged; Protein Methyltransferases; ras Proteins; S-Adenosylhomocysteine; Stomach; Stomach Neoplasms