Inhibition of CDK2, CDK4 and cyclin E and increased expression of p27Kip1 during treatment with interferon-alpha in carcinoid tumor cells.
IFN-alpha has presented antitumor effect in about 50% of carcinoid tumor patients, though the antitumor mechanism of IFN-alpha is still to be elucidated. In this study we demonstrated that IFN-alpha could result in accumulation of S-phase population and upregulation of cyclin-dependent kinase inhibitor (CKI), p27. Moreover, IFN-alpha inhibits DNA synthesis assessed by [3H] thymidine incorporation and colony formation on soft agar. Immunodepletion of p27 increased CDK2- and cyclin E-associated kinase activities. These data suggest that IFN-alpha exerts its antiproliferative effects in the neuroendocrine differentiated cell lines by: 1) inhibition of DNA synthesis and colony formation, 2) upregulation on the mRNA and protein expressions of the CKI, p27.
Zhou
Y
Y
Endocrine Oncology Unit of Internal Medicine, Uppsala University Hospital, Sweden.
Wang
S
S
Gobl
A
A
Oberg
K
K
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000556:secondary; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D019927:Cyclin E / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I / Q000494:pharmacology* / Q000627:therapeutic use; D008207:Lymphatic Metastasis; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D064547:Myxovirus Resistance Proteins; D010190:Pancreatic Neoplasms / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D008869:Microtubule-Associated Proteins; D064547:Myxovirus Resistance Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; 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; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins; D013936:Thymidine