PubMed · 16097243
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Robert J Isaacson. 2005. Mostly for men.. https://doi.org/10.1043/0003-3219(2005)75%5B694%3Amfm%5D2.0.co%3B2
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Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.
The folate antagonist methotrexate (MTX) inhibits synthesis of tetrahydrofolate (THF), pyrimidines and purines, and induces differentiation in several cell types. At 1 microM, MTX reduced proliferation and induced differentiation in HT29 colon cancer cells; the latter effect was augmented (P < 0.001) by thymidine (100 microM) but was reversed (P < 0.001) by the purines, hypoxanthine (Hx; 100 microM) and adenosine (100 microM). In contrast 5-fluoro-uracil (5-FU), a specific thymidylate synthase (TS) inhibitor, had no effect on differentiation, suggesting that MTX-induced differentiation is not due to a reduction in thymidine but to the inhibition of purine biosynthesis. Inhibition of cyclic AMP (cAMP) by RpcAMP (25 microM) further enhanced (P < 0.001) MTX induced differentiation, whereas the cAMP activator forskolin (10 microM) reversed (P < 0.001) MTX induced differentiation. These observations implicate a central role of adenosine and cAMP in MTX induced differentiation. By combining Western blot analysis with liquid chromatography-mass spectrometry (LC-MS)and HPLC analyses we also reveal both the expression and activity of key enzymes (i.e. methionine synthase (MS), s-adenosylhomocysteinase, cystathionine beta-synthase and ornithine decarboxylase) regulating methyl cycle, transsulfuration and polyamine pathways in HT29 colon cancer cells. At 1 microM, MTX induced differentiation was associated with a marked reduction in the intracellular concentrations of adenosine and, consequently, S-adenosylmethionine (SAM), S-adenosylhomocysteine, polyamines and glutathione (GSH). Importantly, the marked reduction in methionine that accompanied MS inhibition following MTX treatment was non-limiting with respect to SAM synthesis. Collectively, these findings indicate that the effects of MTX on cellular differentiation and single carbon metabolism are primarily due to the intracellular depletion of purines.
Previous studies from our laboratory and others have suggested that increased expression of cox-2 is important in the genesis of esophageal adenocarcinoma. In vitro studies suggest that cox-2 regulates expression of the anti-apoptotic protein bcl-2, thus possibly accounting for reduced apoptosis in carcinogenesis. The aim of this study was to investigate the relationship of these 2 genes in the development of Barrett's-associated adenocarcinoma. Histologic sections from endoscopic biopsies or esophagectomy specimens were classified as non-dysplastic Barrett's (n = 30), intraepithelial neoplasia (n = 12) and adenocarcinoma (n = 48). The desired tissue was isolated by laser capture microdissection and expression levels of cox-2 and bcl-2 were measured by quantitative real-time PCR (Taqman). Gene expression levels were compared to samples of the distal esophageal squamous epithelium (n = 55) and reflux-esophagitis (n = 25), without Barrett's or cancer. Expression of both bcl-2 and cox-2 were increased in non-dysplastic Barrett's (p = 0.0077, p = 0.0037), intraepithelial neoplasia (p = 0.0053, p = 0.0220) and adenocarcinoma (p < 0.0001, p < 0.0001) compared to squamous epithelium or reflux-esophagitis. Furthermore, there is a significant correlation between these two genes, especially in carcinoma (p < 0.0001).