| 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. | |
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MedLine Citation:
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PMID: 20354121 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Kota V Ramana; Ravinder Tammali; Satish K Srivastava |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-03-30 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-09 Completed Date: 2010-07-07 Revised Date: 2013-05-29 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 813-24 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0647, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Reductase
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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:
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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:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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