Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice

Amy E. Moran, Daniel H. Hunt, Sara H. Javid, Mark Redston, Adelaide M. Carothers, Monica M. Bertagnolli

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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 (PISK), 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.

Original languageEnglish (US)
Pages (from-to)43261-43272
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number41
DOIs
StatePublished - Oct 8 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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