Down-regulation of increased signal transduction capacity in human cancer cells.
Signal transduction capacity in human cancer cells is constitutively up-regulated by the markedly increased steady-state activities of the three synthetic enzymes, PI kinase, PIP kinase and PLC, which catalyze the conversion of PI to the second messengers IP3 and DAG. This evidence is supported by the elevated concentration of IP3 in human colon, ovarian and breast carcinoma samples and rat hepatocellular carcinomas and sarcoma. The decrease in activities of the two specific phosphatases in the degradative pathway of signal transduction provides an amplified capacity for IP3 production. The elevated second messenger concentrations should lead to increased calcium release and protein kinase C activation. These biochemical alterations should confer selective biological advantages to cancer cells. The malignancy-linked rise in the activity of the signal transduction pathway can be down-regulated by drugs (tiazofurin, ribavirin, tamoxifen) or through inhibition of the kinases by flavonoids (quercetin, genistein) which lead to a reduction of IP3 concentration. As a result, carcinoma cells in culture stop proliferating and are destroyed. The stringent linkage of signal transduction with neoplasia provides novel targets for clinical chemotherapy.
Weber
George
G
Laboratory for Experimental Oncology, Indiana University School of Medicine, 699 West Drive, RR 337, Indianapolis, Indiana 46202-5119, USA. geoweber@iupui.edu
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology*; D004357:Drug Synergism; D019833:Genistein / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D009369:Neoplasms / Q000503:physiopathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D013629:Tamoxifen; D012254:Ribavirin; D015544:Inositol 1,4,5-Trisphosphate; D011794:Quercetin; D019833:Genistein; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D010738:Type C Phospholipases; C033706:tiazofurin