Document Detail

Fhit protein inhibits cell growth by attenuating the signaling mediated by nuclear factor-kappaB in colon cancer cell lines.
MedLine Citation:
PMID:  16733051     Owner:  NLM     Status:  MEDLINE    
Fragile histidine triad (FHIT) gene is involved in the deletions at the 3p14.2 region in various cancers. We investigated the role of Fhit protein in cell growth by examining the signaling pathway affected by Fhit. We used 3 human colon cancer cell lines, SW480, DLD-1 and COLO201, in the study. SW480 cells, in which the expression of Fhit is completely absent, were transfected with pIRES1neo vector (SW/IRES cells), wild-type FHIT vector (SW/FHIT cells) or mt-FHIT (codon 96, His changed to Asn) vector (SW/mt-FHIT cells). The growth of SW/FHIT or SW/mt-FHIT cells was suppressed in comparison with that of parent or SW/IRES cells. Especially, the growth of SW/FHIT cells was considerably suppressed. On the other hand, the silencing of FHIT by an siRNA for it in SW/FHIT or DLD-1 cells harboring Fhit demonstrated that the growth of FHIT siRNA-treated cells was significantly enhanced in comparison with that of the vector control or nonspecific siRNA control. Thus, we found that Fhit negatively contributed to cell growth in the colon cancer cell lines. Moreover, SW/FHIT cells exhibited a higher sensitivity to oxidative stress evoked by inhibitors of mitochondrial electron transport or proteasomes compared with any of the control transfectants. The base line amount of phospho-IkappaB-alpha (p-IkappaB-alpha) was reduced in SW/FHIT cells compared with that in the other transfectants. On the contrary, the FHIT siRNA-treated SW/FHIT and DLD-1 cells exhibited an elevated p-IkappaB-alpha level in an RNAi experiment on FHIT. Perturbation of nuclear factor (NF)-kappaB signaling was strongly suggested by the fact that the wild-type Fhit expressants of SW480 cells tended to be sensitive to sulfasarazine or parthenolide, which are inhibitors of NF-kappaB. The time course of the level of IkappaB kinase (IKK) complex (IKKalpha/beta, phospho-IKKalpha/beta and IKKgamma) after the treatment with TNF-alpha was similar between the transfectants. Although p-IkappaB-alpha and phospho-NF-kappaB p65 (p-NF-kappaB) in SW/FHIT cells responded to TNF-alpha as those in other transfectants, the increase in the levels of p-IkappaB-alpha and p-NF-kappaB after a 5-min treatment was less in SW/FHIT cells than in the other transfectants. These results altogether suggest that Fhit functions as an anti-oncoprotein by inhibiting the phosphorylation of IkappaB-alpha and thereby blocking NF-kappaB signaling.
Yoshihito Nakagawa; Yukihiro Akao
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-04-25
Journal Detail:
Title:  Experimental cell research     Volume:  312     ISSN:  0014-4827     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-17     Completed Date:  2006-08-18     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2433-42     Citation Subset:  IM    
Department of Medical Oncology, Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
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MeSH Terms
Acid Anhydride Hydrolases / genetics,  metabolism*
Cell Line, Tumor
Cell Proliferation
Colonic Neoplasms / pathology*
DNA, Complementary / genetics
Down-Regulation / genetics
Exons / genetics
Gene Expression Regulation, Neoplastic
I-kappa B Kinase / metabolism
NF-kappa B / metabolism*
Neoplasm Proteins / genetics,  metabolism*
RNA Interference
RNA, Messenger / genetics,  metabolism
Signal Transduction*
Tumor Cells, Cultured
Reg. No./Substance:
0/DNA, Complementary; 0/NF-kappa B; 0/Neoplasm Proteins; 0/RNA, Messenger; 0/fragile histidine triad protein; EC B Kinase; EC 3.6.-/Acid Anhydride Hydrolases

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