Document Detail


Inhibition of aldose reductase prevents growth factor-induced G1-S phase transition through the AKT/phosphoinositide 3-kinase/E2F-1 pathway in human colon cancer cells.
MedLine Citation:
PMID:  20354121     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Colon cancer is the leading cause of cancer death in both men and women worldwide. The deregulated cell cycle control or decreased apoptosis of normal epithelial cells leading to uncontrolled proliferation is one of the major features of tumor progression. We have previously shown that aldose reductase (AR), a NADPH-dependent aldo-keto reductase, has been shown to be involved in growth factor-induced proliferation of colon cancer cells. Herein, we report that inhibition of AR prevents epidermal growth factor (EGF)- and basic fibroblast growth factor (bFGF)-induced HT29 cell proliferation by accumulating cells at G(1) phase of cell cycle. Similar results were observed in SW480 and HCT-116 colon cancer cells. Treatment of HT29 cells with AR inhibitor, sorbinil or zopolrestat, prevented the EGF- and bFGF-induced DNA binding activity of E2F-1 and phosphorylation of retinoblastoma protein. Inhibition of AR also prevented EGF- and bFGF-induced phosphorylation of cyclin-dependent kinase (cdk)-2 and expression of G(1)-S transition regulatory proteins such as cyclin D1, cdk4, proliferating cell nuclear antigen, cyclin E, and c-myc. More importantly, inhibition of AR prevented the EGF- and bFGF-induced activation of phosphoinositide 3-kinase/AKT and reactive oxygen species generation in colon cancer cells. Further, inhibition of AR also prevented the tumor growth of human colon cancer cells in nude mouse xenografts. Collectively, these results show that AR mediates EGF- and bFGF-induced colon cancer cell proliferation by activating or expressing G(1)-S phase proteins such as E2F-1, cdks, and cyclins through the reactive oxygen species/phosphoinositide 3-kinase/AKT pathway, indicating the use of AR inhibitors in the prevention of colon carcinogenesis. Mol Cancer Ther; 9(4); 813-24. (c)2010 AACR.
Authors:
Kota V Ramana; Ravinder Tammali; Satish K Srivastava
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-03-30
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-07-07     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  813-24     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0647, USA.
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Reductase / antagonists & inhibitors*,  metabolism
Animals
Benzothiazoles / pharmacology
Cell Cycle / drug effects*
Cell Cycle Proteins / genetics,  metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / enzymology*,  genetics,  pathology
DNA, Neoplasm / metabolism
E2F1 Transcription Factor / genetics,  metabolism*
G1 Phase / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
Imidazolidines / pharmacology
Intercellular Signaling Peptides and Proteins / pharmacology*
Mice
Neoplasm Proteins / genetics,  metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation / drug effects
Phthalazines / pharmacology
Protein Binding / drug effects
Proto-Oncogene Proteins c-akt / metabolism*
RNA, Messenger / genetics,  metabolism
Retinoblastoma Protein / metabolism
S Phase / drug effects
Signal Transduction / drug effects
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA 129383/CA/NCI NIH HHS; DK36118/DK/NIDDK NIH HHS; GM 71036/GM/NIGMS NIH HHS; R01 CA129383-03/CA/NCI NIH HHS; R01 GM071036-05/GM/NIGMS NIH HHS; R37 DK036118-21/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Benzothiazoles; 0/Cell Cycle Proteins; 0/DNA, Neoplasm; 0/E2F1 Transcription Factor; 0/E2F1 protein, human; 0/Imidazolidines; 0/Intercellular Signaling Peptides and Proteins; 0/Neoplasm Proteins; 0/Phthalazines; 0/RNA, Messenger; 0/Retinoblastoma Protein; 1PV3S9WP3D/zopolrestat; 68367-52-2/sorbinil; EC 1.1.1.21/Aldehyde Reductase; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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