Characterization and Selective Targeting of Aneuploid Human Colonic Epithelial Cells

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2012-11-28

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Ly, Peter 1986-

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Abstract

Aneuploidy, an abnormal number of chromosomes, occurs in the vast majority of sporadic colorectal cancer patients. Despite this observation, the cellular advantages conferred by recurring cytogenetic alterations are poorly understood and targeted therapies selective to aneuploid cells are currently non-existent. Here, we provide evidence that serum-free passage of originally diploid, immortalized human colonic epithelial cells give rise to the acquisition of trisomy 7 (1CT+7), an aneuploidy detected in over 40% of colorectal adenomas. Pre-existing 1CT+7 cells within the original population were undetectable through GTG-banding and fluorescent in situ hybridization analysis, suggesting a conversion of diploid cells to an aneuploid state. Compared to their isogenic diploid counterpart, 1CT+7 cells express higher levels of the epidermal growth factor receptor (EGFR, located on chromosome 7p). Treatment with the pharmacological adenosine analog 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) completely halted proliferation of 1CT+7 cells and reduced both metabolic consumption and production in vitro. Unexpectedly, treatment of 1CT+7 cells with AICAR led to a reversible 3.5-fold reduction 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 cell lines in vitro and in xenograft tumors in vivo. Our data collectively supports the compound AICAR as a novel inhibitor of EGFR protein abundance and as a potential anticancer agent for aneuploidy-driven colorectal cancer. In summary, we have isolated and characterized isogenic human colonic epithelial cells that represent recurrent chromosomal acquisitions in sporadic colorectal cancer and demonstrate how it may be possible to selectively target these cells for therapeutic intervention.

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