Aneuploid human colonic epithelial cells are sensitive to AICAR-induced growth inhibition through EGFR degradation

P. Ly, S. B. Kim, A. A. Kaisani, G. Marian, W. E. Wright, J. W. Shay

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3139-3146
Number of pages8
JournalOncogene
Volume32
Issue number26
DOIs
StatePublished - Jun 27 2013

Keywords

  • AICAR
  • aneuploidy; EGFR
  • chromosomal instability
  • trisomy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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