Document Detail


Differing effects of staurosporine and UCN-01 on RB protein phosphorylation and expression of lung cancer cell lines.
MedLine Citation:
PMID:  8960146     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The retinoblastoma gene product (RB protein) plays a key role in the progression of the cell cycle from G1 to S phase in normal and neoplastic cells. The activity of RB is regulated by phosphorylation and dephosphorylation with cell-cycle-dependent protein kinases. We investigated the effect of the protein kinase inhibitors, staurosporine and 7-hydroxy-staurosporine (UCN-01), on RB protein expression of N417 small cell lung cancer cells (absent RB), H209 small cell lung cancer cells (mutant RB), and Ma-31 non-small cell lung cancer cells (wild-type RB), using immunologic blotting. Staurosporine and UCN-01 each suppressed the growth of N417, H209 and Ma-31 cells in a dose-dependent manner in MTT assay. IC50 values of staurosporine for N417, H209 and Ma-31 cells were 54, 29 and 602 nM, respectively. IC50 values of UCN-01 for N417, H209 and Ma-31 cells were 737, 181 and 2,197 nM, respectively. Exposure to staurosporine and UCN-01 for 72 h each suppressed the level of expression and altered the ratio of phosphorylated/dephosphorylated RB protein (ppRB/pRB) of Ma-31 cells. Conversely, these agents increased the expression level of RB protein at concentrations less than IC50, and did not change phosphorylation status of mutant RB protein of H209 cells at the concentrations studied. A time course study demonstrated that exposure to the IC50 concentration of staurosporine for 48-72 h increased the ratio of ppRB/ pRB of Ma-31 cells, while exposure to the IC50 concentration of UCN-01 decreased that ratio. UCN-01 increased % cells in G2 + M phase and decreased % cells in S phase, while staurosporine increased % cells in G1 phase and decreased % cells in G2 + M phase. UCN-01 did not induce apoptosis (DNA content < 2 N) of Ma-31 cells, but staurosporine induced it. These findings suggest that the differing effects of staurosporine and UCN-01 on RB protein expression and cell cycle phases of lung cancer cells may explain their differing in vivo antitumor effect of staurosporine and UCN-01 despite their similar chemical structures.
Authors:
E Shimizu; M R Zhao; H Nakanishi; A Yamamoto; S Yoshida; M Takada; T Ogura; S Sone
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology     Volume:  53     ISSN:  0030-2414     ISO Abbreviation:  Oncology     Publication Date:    1996 Nov-Dec
Date Detail:
Created Date:  1997-01-07     Completed Date:  1997-01-07     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  0135054     Medline TA:  Oncology     Country:  SWITZERLAND    
Other Details:
Languages:  eng     Pagination:  494-504     Citation Subset:  IM    
Affiliation:
Third Department of Internal Medicine, Tokushima University School of Medicine, Japan.
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MeSH Terms
Descriptor/Qualifier:
Alkaloids / chemistry,  pharmacology*
Cell Cycle / drug effects,  physiology
Cell Division / drug effects
DNA, Neoplasm / analysis
Enzyme Inhibitors / chemistry,  pharmacology*
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / drug therapy,  metabolism*
Phosphorylation / drug effects
Protein Kinase C / antagonists & inhibitors*
Retinoblastoma Protein / drug effects,  metabolism*
Staurosporine / chemistry,  pharmacology*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Alkaloids; 0/DNA, Neoplasm; 0/Enzyme Inhibitors; 0/Retinoblastoma Protein; 62996-74-1/Staurosporine; 7BU5H4V94A/7-hydroxystaurosporine; EC 2.7.11.13/Protein Kinase C

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