Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells.
Prostate carcinoma cells express high levels of interleukin-6 (IL-6) and IL-6 receptor. In this study, we examined the effect of IL-6 on LNCaP human prostate carcinoma cells. IL-6 induces G1 growth arrest of LNCaP. Following IL-6 treatment of LNCaP, Western blot analysis showed that the protein levels of cyclin-dependent kinase-2 (CDK2), CDK4, and CDK6 were decreased, while accumulation of CDK inhibitor p27(Kip1) was rapidly and markedly induced. In vitro kinase assays revealed that the CDK-associated histone H1 and CDK4- and CDK6-associated pRb kinase activities were significantly inhibited in IL-6-treated LNCaP. Further, a significant amount of p27(Kip1) was co-precipitated with CDK2, CDK4 and CDK6, as detected in immunoprecipitation experiments. Thus, IL-6-induced G1 arrest appears to be due to the accumulation of p27(Kip1). In addition, IL-6-treated LNCaP cells induced neuron-like morphological changes. Since neuroendocrine differentiation is observed in most prostate carcinomas, these findings raise the possibility that IL-6 may be involved in neuroendocrine differentiation in vivo.
Mori
S
S
Department of Microbiology and Immunology, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, California, 90095-1747, USA.
Murakami-Mori
K
K
Bonavida
B
B
D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006657:Histones; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases