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Insulin-like growth factor binding protein-3 induces G1 cell cycle arrest with inhibition of cyclin-dependent kinase 2 and 4 in MCF-7 human breast cancer cells.

 H.-S. Kim  ;  W. J. Lee  ;  S. W. Lee  ;  H.-W. Chae  ;  D. H. Kim  ;  Y. Oh 
 HORMONE AND METABOLIC RESEARCH, Vol.42(3) : 165-172, 2010 
Journal Title
Issue Date
Breast Neoplasms/enzymology* ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology* ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin D1/genetics ; Cyclin D1/metabolism ; Cyclin-Dependent Kinase 2/antagonists & inhibitors* ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors* ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase Inhibitor Proteins/metabolism ; Ecdysterone/analogs & derivatives ; Ecdysterone/pharmacology ; Female ; G1 Phase*/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Proteins/metabolism* ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Insulin-like growth factor binding protein (IGFBP)-3 has been shown to potently inhibit proliferation of various cell types in an insulin-like growth factor (IGF)-independent manner. We have previously shown that IGFBP-3 induces apoptosis in an IGF-independent manner through the activation of caspases involved in a death receptor-mediated pathway in MCF-7 human breast cancer cells. In the present study, we present further evidence that IGFBP-3 inhibits cell proliferation through the induction of cell cycle arrest in the same cell line. Induction of IGFBP-3 in MCF-7 cells inhibited cell proliferation whereas presence of small interfering RNA against IGFBP-3 abolished cell inhibitory effect of IGFBP-3, suggesting that the observed growth inhibition is specific. Flow cytometry analysis showed that induced expression of IGFBP-3 led to an arrest of the cell cycle in G1-S phase. Western immunoblot analysis showed a significant decrease in the levels of the cell cycle-regulated proteins such as cyclin D1, cyclin D3, cyclin E, cyclin A, cyclin-dependent kinase (CDK) 2, CDK4, retinoblastoma protein (pRB), and phosph-pRB, suggesting a possible mechanism for cell cycle arrest by IGFBP-3. Northern blot analysis and real-time quantitative PCR demonstrated a significant decrease in gene expression of cyclin D1. Additional phosphorylation assay showed that IGFBP-3 decreased the phosphorylation activity of CDK2 and CDK4. These results show that cellular production of IGFBP-3 leads to G1 cell cycle arrest with inhibition of CDK2 and CDK4. Taken together, IGFBP-3 exerts its growth inhibitory action through not only induction of apoptosis but also the G1 cell cycle arrest in human breast cancer cells.
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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Duk Hee(김덕희)
Kim, Ho Seong(김호성) ORCID logo https://orcid.org/0000-0003-1135-099X
Lee, Sun Woo(이선우)
Chae, Hyun Wook(채현욱) ORCID logo https://orcid.org/0000-0001-5016-8539
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