Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

• Published in: The Journal of biological chemistry 2004-10, Vol.279 (41), p.43261-43272
• Main Authors: Moran, Amy E, Hunt, Daniel H, Javid, Sara H, Redston, Mark, Carothers, Adelaide M, Bertagnolli, Monica M
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adenoma - metabolism; Adenoma - pathology; Adenomatous Polyposis Coli Protein - deficiency; Alleles; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Clathrin - metabolism; Colorectal Neoplasms - metabolism; Cyclooxygenase 2; Dinoprostone - metabolism; Disease Progression; Enterocytes - metabolism; Enzyme-Linked Immunosorbent Assay; ErbB Receptors - metabolism; Genes, APC; HeLa Cells; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Intestinal Mucosa - metabolism; Intestine, Small - metabolism; Isoenzymes - metabolism; Jurkat Cells; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Mutation; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Prostaglandin-Endoperoxide Synthases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Recurrence; Signal Transduction; src-Family Kinases - metabolism; Tissue Distribution; Transcriptional Activation; Tyrosine - chemistry; Ubiquitin - metabolism; Up-Regulation; Vanadates - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M404276200

Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc +/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85α, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E 2 (PGE 2 ) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE 2 expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc +/+ and Apc Min/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.