Effects of interferon alpha on the expression of p21cip1/waf1 and cell cycle distribution in carcinoid tumors.
Interferon alpha (IFN-alpha) has been shown to produce antitumor effects in 50-80% of carcinoid tumor patients and has demonstrated anti-proliferative effects in carcinoid tumor cells, but the mechanism is not well established. This study presents evidence that in a carcinoid tumor cell line, Bon1, IFN-alpha increases the expression of p21 and promotes nuclear translocation of endogenous p21. Furthermore, immunoprecipitation experiments demonstrated that p21 formed immuno-complexes with Stat1 and Stat2 in the nucleus of cells. Interferon alpha can decrease G1- and G2-phase cells, but increase S-phase population. The p21 mRNA expression is inversely correlated to the G1 population (r = -0.933, P < 0.05) and positively correlated to the S-phase population (r = 0.901, P < 0.05). In addition, IFN-alpha inhibited cyclin dependent kinases (CDK), CDK2-, CDK3-, CDK4-, and cyclin E- but not cyclin A-associated kinase activities. Immunodepletion of p21 resulted in a significant enhancement of CDK3 kinase activity (approximately 1.6-fold increase). These results suggest that the mechanism of antitumor and cell cycle regulation of IFN-alpha in carcinoid tumors may, at least in part, be p21-dependent. Based on these results, we conclude that IFN-alpha exerts antitumor effects by increased p21 expression in neuroendocrine tumors.
Zhou
Yinghua
Y
Department of Medical Sciences, Endocrine Oncology Unit of Internal Medicine, Uppsala University Hospital, S751 85 Uppsala, Sweden.
Wang
Shu
S
Yue
Bai-Gong
BG
Gobl
Anders
A
Oberg
Kjell
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002276:Carcinoid Tumor / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000494:pharmacology; D016213:Cyclins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016898:Interferon-alpha; D018844:Cyclin-Dependent Kinases