Regulation of signal transduction activity in normal and cancer cells.
The purpose of this investigation is to clarify critical aspects of the behavior and regulation of signal transduction activity in normal and cancer cells.


METHODS
Signal transduction activity was determined by measuring the steady-state activity of the three synthetic enzymes involved in the conversion of 1-phosphatidylinositol to IP3, PI 4-kinase, PI 4-phosphate 5-kinase and phospholipase C. These enzymic activities were opposed by the activities of the degradative enzymes, 4-phosphatase and 5-phosphatase.


RESULTS
We observed in hepatocellular carcinomas the operation of an integrated imbalance in signal transduction which was manifested in the up-regulation of the steady-state activities of the three synthetic enzymes and in the reduction of the activities of the two catabolic phosphatases. As a consequence of this enzyme imbalance there was an increase in the concentration of IP3 in hepatomas. Increased IP3 levels were also observed in numerous human carcinomas in clinical samples and in tissue culture cells. The signal transduction activity was subject to nutritional regulation and to drug action. The elevated signal transduction activity, as measured by the IP3 concentration, was down-regulated in a time- and dose-dependent fashion by the anticancer drug, tiazofurin, by the flavonoids, quercetin and genistein, and by the anti-estrogen receptor, tamoxifen.


CONCLUSIONS
Our studies show that signal transduction activity is stringently linked with transformation and progression in rat and human carcinomas. Down-regulation of signal transduction activity by various drugs led to a marked reduction of IP3 concentration and then to apoptosis and induced differentiation.
Weber
G
G
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5119, USA.
Shen
F
F
Yang
H
H
Prajda
N
N
Li
W
W
D000818:Animals; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D013629:Tamoxifen; D012254:Ribavirin; D015544:Inositol 1,4,5-Trisphosphate; D011794:Quercetin; D019833:Genistein; C033706:tiazofurin