Regulation of cyclooxygenase-2 pathway by HER2 receptor

Ratna Vadlamudi, Mahitosh Mandal, Liana Adam, Gideon Steinbach, John Mendelsohn, Rakesh Kumar

Research output: Contribution to journalArticle

202 Scopus citations

Abstract

Emerging lines of evidence suggest that in addition to growth factors, the process of colorectal tumorigenesis may also be driven by the upregulation of the inducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to PGEs. The present study was undertaken to investigate the expression and activation of the HER family members, and to explore the regulation of COX-2 expression by the HER2 pathway in human colorectal cancer cells. Here, we report that human colorectal cancer cell lines express abundant levels of HER2 and HERS receptors, and are growth-stimulated by recombinant neu-differentiation factor-beta 1 (NDF). NDF-treatment of colorectal cancer cells was accompanied by increased tyrosine phosphorylation and heterodimerization of HERS with HER2. In addition, we demonstrated that HER2 and HER3 receptors in colorectal cancer cells are constitutively phosphorylated on tyrosine residues and form heterodimeric complexes in the absence of exogenous NDF. Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/HER3 heterodimers, and the unexpected reduction of COX-2 expression. Activation of the HER2/HER3 pathway by NDF induced the activation of COX-2 promoter, expression of COX-2 mRNA, COX-2 protein and accumulation of prostaglandin E2 in the culture medium. Finally, we demonstrated that NDF promotes the ability of colorectal cancer cells to survive in an extracellular matrix milieu, such as Matrigel, and also to invade through a 8 μm porous membrane. These biological activities of NDF and its stimulation of cell proliferation are blocked by a specific inhibitor of COX-2. Taken together, our findings provide the first biochemical evidence of a possible role of the COX-2 pathway in the mitogenic action of NDF in colorectal cancer cells where it may be constitutively upregulated due to the autocrine/paracrine activation of HER2/HER3 heterodimers.

Original languageEnglish (US)
Pages (from-to)305-314
Number of pages10
JournalOncogene
Volume18
Issue number2
DOIs
StatePublished - Jan 14 1999
Externally publishedYes

Keywords

  • COX-2
  • Colon cancer
  • NDF

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Vadlamudi, R., Mandal, M., Adam, L., Steinbach, G., Mendelsohn, J., & Kumar, R. (1999). Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene, 18(2), 305-314. https://doi.org/10.1038/sj.onc.1202307