Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells.
Classical cytotoxic therapy has been minimally useful in the treatment of hepatocellular carcinoma. In an effort to develop a new approach to the treatment of this neoplasm, we have investigated the signal transduction pathways regulating the growth of human hepatoma cells. In the data reported here, cyclic AMP (cAMP), a negative growth regulator for many cells of epithelial origin, induced G1 synchronization and apoptosis in the HepG2 human hepatoma cell line. The effects of cAMP on the components of the G1/S transition were analyzed. There was no detectable effect of two different cAMP analogs, 8-bromo cAMP or dibutyryl cAMP on the level of the D-type cyclins, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, p53, or the cyclin-dependent kinase inhibitors p21 or p27. In contrast, the cAMP analogs induced a dramatic downregulation of cyclin A protein, cyclin A messenger RNA, and cyclin A-dependent kinase activity. Cyclin A-dependent kinase has been shown to be required for the G1-S transition. Furthermore, cyclin A deregulation has been implicated in the pathogenesis of hepatocellular carcinoma. The data reported here suggest a novel signal transduction-based approach to hepatoma therapy.
Lee
J
J
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Building 10, Room 12N230, Bethesda, MD 20892, USA.
Choi
Y H
YH
Nguyen
P
P
Kim
J S
JS
Lee
S J
SJ
Trepel
J B
JB
D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D006528:Carcinoma, Hepatocellular; D002453:Cell Cycle / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology*; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D019925:Cyclin A; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases