Document Detail


Growth arrest induced by C75, A fatty acid synthase inhibitor, was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma.
MedLine Citation:
PMID:  16855382     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
C75, a well-known fatty acid synthase (FAS) inhibitor, has been shown to possess potent anti-cancer activity in vitro and in vivo. In this study, we reveal that C75 is a cell cycle arrest inducer and explore the potential mechanisms for this effect in hepatocellular carcinoma (HCC) cell lines with abundant FAS expression: HepG2 and SMMC7721 cells with wt-p53, and Hep3B cells with null p53. The results showed FAS protein expression and basal activity levels were higher in HepG2 cells than in the other two HCC cell lines. Treatment with C75 inhibited FAS activity within 30 min of administration and induced G(2) phase arrest accompanied by p53 overexpression in HepG2 and SMMC7721 cells. By contrast, C75 triggered G(1) phase arrest in Hep3B cells, and RNA interference targeting p53 did not attenuate C75-induced G(2) arrest in HepG2 cells. Similarly, p53 overexpression via p53 plasmid transfection did not affect C75-induced G(1) phase arrest in Hep3B cells. However, we observed a clear correlation between p38 MAPK activation triggered by C75 and the induction of cell cycle arrest in all three HCC cells. Furthermore, treatment with the p38 MAPK inhibitor SB203580 reduced p38 MAPK activity and cell cycle arrest, and also partially restored cyclin A, cyclin B1, cyclin D1 and p21 protein levels. Collectively, it was p38 MAPK but not p53 involved in C75-mediated tumor cell growth arrest in HCC cells.
Authors:
Yan Gao; Li-Ping Lin; Cai-Hua Zhu; Yi Chen; Yong-Tai Hou; Jian Ding
Publication Detail:
Type:  Journal Article     Date:  2006-08-03
Journal Detail:
Title:  Cancer biology & therapy     Volume:  5     ISSN:  1538-4047     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-10-13     Completed Date:  2007-01-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  978-85     Citation Subset:  IM    
Affiliation:
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
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MeSH Terms
Descriptor/Qualifier:
4-Butyrolactone / analogs & derivatives*,  pharmacology
Antigens, CD95 / metabolism
Blotting, Western
Carcinoma, Hepatocellular / genetics,  metabolism*,  pathology
Cell Proliferation
Cyclin A / metabolism
Cyclin B / metabolism
Cyclin B1
Cyclin D1 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Fatty Acid Synthetase Complex / antagonists & inhibitors*
Flow Cytometry
G2 Phase / drug effects*
Humans
Immunoprecipitation
Liver Neoplasms / genetics,  metabolism*,  pathology
Plasmids / genetics
RNA, Small Interfering / pharmacology
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / antagonists & inhibitors,  genetics,  metabolism*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  genetics,  metabolism*
Chemical
Reg. No./Substance:
0/4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; 0/Antigens, CD95; 0/CCNB1 protein, human; 0/Cyclin A; 0/Cyclin B; 0/Cyclin B1; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 136601-57-5/Cyclin D1; 96-48-0/4-Butyrolactone; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 6.-/Fatty Acid Synthetase Complex
Comments/Corrections
Comment In:
Cancer Biol Ther. 2006 Aug;5(8):986-7   [PMID:  16998303 ]

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