Regulation of Cyclooxygenase-2 pathway by HER2 receptor

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 HER3 receptors, and are growth-stimulated by recombinant neu-di erentiation factor-beta 1 (NDF). NDF-treatment of colorectal cancer cells was accompanied by increased tyrosine phosphorylation and heterodimerization of HER3 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 mm porous membrane. These biological activities of NDF and its stimulation of cell proliferation are blocked by a speci®c inhibitor of COX-2. Taken together, our ®ndings provide the ®rst 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.

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

“…Second, COX-2 directly stimulates tumor cell survival, proliferation, migration and invasion in conjunction with oncogenic pathways. For example, activation of HER2/HER3 heterodimers in CRC cells induces COX-2 expression and PGE 2 production (Vadlamudi et al, 1999), which transactivates the epidermal growth factor receptor and activates ERK, resulting in increased cell migration and proliferation (Pai et al, 2002;Shao et al, 2003). COX-2 also cross-talks with the Wnt pathway (Wang et al, 2004).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…In colorectal cancer cell lines, ERBB2 and ERBB3 generally show high expression and constitutive activation and dimer formation, 141 which is further enhanced by treatment with NRG, leading to stimulation and enhanced invasiveness. 333 Stimulation of COX-2 gene expression was part of the mechanisms of these effects of NRG. The EGFR may also be important, as sensitivity of colon cancer cell lines to growth suppression by the EGFR-specific inhibitor erlotinib (Tarceva) correlated closely with expression of ERBB3.…”

Curcumin and its Analogues (PGV-0 and PGV-1) Enhance Sensitivity of Resistant MCF-7 Cells to Doxorubicin through Inhibition of HER2 and NF-kB Activation

“…Inhibition of Epidermal Growth Factor Receptor (EGFR), HER2 and Estrogen Receptor (ER) in breast cancer cells, has been shown to inhibit the growth and development of breast cancer cells (Vora et al, 2009). Overexpression of HER2 in the biliary epithelium of transgenic mice and in colorectal cancer cells led to an increase of COX-2 expression (Vadlamudi, 1999;Kiguchi et al, 2001). Doxorubicin (Dox) is a chemotherapeutic agent used to treat breast cancer.…”