Document Detail


The chemopreventive agent alpha-difluoromethylornithine blocks Ki-ras-dependent tumor formation and specific gene expression in Caco-2 cells.
MedLine Citation:
PMID:  15057874     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutation of the Kirsten-ras (Ki-ras) proto-oncogene occurs frequently in colorectal cancers. alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), inhibits Ki-ras transformation and colon tumorigenesis in carcinogen-treated animal models by mechanisms yet to be elucidated. Caco-2 cells transfected with an activated Ki-ras, but not parental cells, formed tumors in severe combined immunodeficient (SCID) mice. DFMO treatment (2% in drinking water) prevented tumor growth. Gene expression profiling was performed to identify Ki-ras-and DFMO-dependent patterns of gene expression. Microarray results were validated with real-time or semi-quantitative RT-PCR and/or Western blot analysis. Genes upregulated in Caco-2 cells expressing an activated Ki-ras encoded cytoskeletal-, transport-, protease-, and gap junction-associated proteins. These genes are important for normal development and maintenance of colonic epithelial tissue. Caco-2 cells transfected with an activated Ki-ras displayed increased expression of the integrin alpha 1 (INGA1) and enhanced cell migration on laminin. These parameters were unaffected by DFMO, but Ki-ras-dependent migration was inhibited by INGA1 antibodies. Other Ki-ras-dependent, but DFMO-independent, genes included transglutaminase (TGase) and kallikrein 6 (KLK6). Ki-ras-transfected cells also expressed increased levels of connexin43 (Cx43) (RNA and protein), tight junction protein, and endothelin 1. DFMO reversed these increases. The results indicated that the Ki-ras oncogene caused changes in experimental cell migration and cell-cell communication genes and that some of these changes could be reversed by DFMO.
Authors:
Natalia A Ignatenko; Hui Zhang; George S Watts; Bethany A Skovan; David E Stringer; Eugene W Gerner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular carcinogenesis     Volume:  39     ISSN:  0899-1987     ISO Abbreviation:  Mol. Carcinog.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-04-01     Completed Date:  2004-04-30     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8811105     Medline TA:  Mol Carcinog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  221-33     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Wiley-Liss, Inc.
Affiliation:
Department of Cell Biology and Anatomy, Arizona Cancer Center, The University of Arizona, Tucson, Arizona, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / therapeutic use*
Caco-2 Cells
Cell Communication
Cell Movement
Colonic Neoplasms / genetics,  metabolism,  prevention & control*
Eflornithine / therapeutic use*
Gene Expression Profiling
Gene Expression Regulation / drug effects*
Genes, ras / drug effects*
Humans
Laminin / metabolism
Mice
Mice, SCID
Neoplasm Proteins / genetics,  metabolism
Oligonucleotide Array Sequence Analysis
Ornithine Decarboxylase / antagonists & inhibitors,  metabolism
Transfection
Grant Support
ID/Acronym/Agency:
CA 23074/CA/NCI NIH HHS; CA 72008/CA/NCI NIH HHS; CA 95060/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Laminin; 0/Neoplasm Proteins; 70052-12-9/Eflornithine; EC 4.1.1.17/Ornithine Decarboxylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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