Document Detail


Aneuploid human colonic epithelial cells are sensitive to AICAR-induced growth inhibition through EGFR degradation.
MedLine Citation:
PMID:  22890317     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Trisomy for chromosome 7 is frequently observed as an initiating event in sporadic colorectal cancer. Although unstable chromosome numbers and recurrent aneuploidies drive a large fraction of human cancers, targeted therapies selective to pre-neoplastic trisomic cells are non-existent. We have previously characterized a trisomy 7 cell line (1CT+7) spontaneously derived from normal diploid human colonic epithelial cells that aberrantly expresses the epidermal growth factor receptor (EGFR, chromosome 7p11). Recent studies identified AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) as a pharmacological inhibitor of aneuploid murine fibroblast proliferation. Here, we report that AICAR induces profound cytostatic and metabolic effects on 1CT+7 cells, but not on their isogenic diploid counterpart. Dose-response experiments indicate that 1CT+7 cells are fourfold preferentially sensitive to AICAR compared to diploid cells. Unexpectedly, treatment of 1CT+7 cells with AICAR led to a reversible 3.5-fold reduction (P=0.0025) in EGFR overexpression. AICAR-induced depletion of EGFR protein can be abrogated through inhibition of the proteasome with MG132. AICAR also heavily promoted EGFR ubiquitination in cell-based immunoprecipitation assays, suggesting enhanced degradation of EGFR protein mediated by the proteasome. Moreover, treatment with AICAR reduced EGFR protein levels in a panel of human colorectal cancer cells in vitro and in xenograft tumors in vivo. Our data collectively support the pharmacological compound AICAR as a novel inhibitor of EGFR protein abundance and as a potential anticancer agent for aneuploidy-driven colorectal cancer.
Authors:
P Ly; S B Kim; A A Kaisani; G Marian; W E Wright; J W Shay
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-13
Journal Detail:
Title:  Oncogene     Volume:  32     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-27     Completed Date:  2013-09-03     Revised Date:  2014-04-15    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  3139-46     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aminoimidazole Carboxamide / analogs & derivatives*,  pharmacology
Aneuploidy
Animals
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Colon / drug effects,  metabolism
Colorectal Neoplasms / drug therapy*
Epithelial Cells / drug effects*,  metabolism
Humans
Hypoglycemic Agents / pharmacology
Intestinal Mucosa / drug effects*,  metabolism
Leupeptins / pharmacology
Mice
Neoplasm Transplantation
Proteasome Endopeptidase Complex / metabolism
Receptor, Epidermal Growth Factor / metabolism*
Ribonucleotides / pharmacology*
Transplantation, Heterologous
Trisomy
Ubiquitination
Grant Support
ID/Acronym/Agency:
CA70907/CA/NCI NIH HHS; P30 CA142543/CA/NCI NIH HHS; P50 CA070907/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Hypoglycemic Agents; 0/Leupeptins; 0/Ribonucleotides; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 360-97-4/Aminoimidazole Carboxamide; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.25.1/Proteasome Endopeptidase Complex; F0X88YW0YK/AICA ribonucleotide
Comments/Corrections

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


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