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J Thorac Cardiovasc Surg 2005;130:1484-1485
© 2005 The American Association for Thoracic Surgery

Letter to the Editor

Association between cyclooxygenase and epidermal growth factor receptor pathways in non–small cell lung cancer

^a Department of Cardiovascular Surgery, Siyami Ersek Thoracic and Cardiovascular Education and Research Hospital, Istanbul, Turkey
^b 8181 Fannin St No. 728, Houston, TX 77054
^c Department of Internal Medicine, Marmara University Medical School, Istanbul, Turkey
^d Department of Medical Oncology, Hacettepe University Medical School, Ankara, Turkey

To the Editor:

We read with great interest the article by Sievers and associates. ¹ In their orthotopic murine model of lung cancer with adenocarcinoma, they showed inhibition of tumor growth with a low-dose cyclooxygenase-2 (COX-2) inhibitor, celecoxib. In their article, they discussed different mechanisms of association between COX-2 inhibition and attenuation of tumor growth in non–small cell lung cancer (NSCLC), and we want to propose another. COX (or prostaglandin endoperoxide synthase) catalyzes the conversion of arachidonic acid to prostaglandin (PG) H₂. This unstable endoperoxide is then converted into PGE₂, PGI₂, PGD₂, PGF₂, or thromboxane A₂ by each respective PG synthase. Most tumors that express COX have been found to contain high levels of PGE₂ and the microsomal PGE synthase enzyme. Presumably, these bioactive lipid products of COX, such as PGE2, are responsible for some of the proneoplastic effects mediated by this enzyme. ² The epidermal growth factor receptor (EGFR) is a member of the ErbB family of transmembrane tyrosine kinase receptors. The expression of EGFR is common in a number of normal epithelial tissues, and the expression of EGFR is elevated in several solid tumors. In NSCLC, overexpression of EGFR has been reported to be present in more than 50% of cases in several series. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In addition to this, several retrospective studies have identified the expression of EGFR as a negative prognostic factor in patients with resected early NSCLC. ³ Sheng and colleagues ⁴ found that PGE₂ initially binds to its cognate receptor, EP4, in LS-174T cells, which in turn activates signals that led to dramatic changes in cell biology. One study demonstrated that the PGE₂-induced migration and invasion occur by rapid transactivation and phosphorylation of EGFR in developing carcinoma cells. ⁵ Within minutes after treatment, PGE₂ induces the activation of Akt. This effect is completely abolished by EGFR-specific tyrosine kinase inhibitors, providing evidence for the role of the EGFR in this response. The rapid transactivation of EGFR occurs by an intracellular Src-mediated event, but not through the release of an extracellular epidermal growth factor–like ligand. These results suggest that the early effects of COX-2–derived PGE₂ are in part mediated by EGFR, and this transactivation is responsible for subsequent downstream effects, including the stimulation of cell migration and invasion. ⁵ In the light of this information, we propose that celecoxib may inhibit downstream signaling of EGFR by decreasing the COX-2 protein and PGE₂ levels, resulting in tumor growth inhibition in NSCLC.

	References

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1. Sievers EM, Bart RD, Backhus LM, Lin Y, Starnes M, Castanos R, et al. Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect. J Thorac Cardiovasc Surg 2005;129:1242-1249.[Abstract/Free Full Text]
   
2. Gupta RA, Tejada LV, Tong BJ, Das SK, Morrow JD, Dey SK, et al. Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor production in ovarian cancer. Cancer Res 2003;63:906-911.[Abstract/Free Full Text]
   
3. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787-2799.[Abstract/Free Full Text]
   
4. Sheng H, Shao J, Washington MK, DuBois RN. Prostaglandin E₂ increases growth and motility of colorectal carcinoma cells. J Biol Chem 2001;276:18075-18081.[Abstract/Free Full Text]
   
5. Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin E₂ regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278:35451-35457.[Abstract/Free Full Text]
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mehmet Ates Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ates, M. Articles by Altundag, K. Search for Related Content PubMed PubMed Citation Articles by Ates, M. Articles by Altundag, K. Related Collections Lung - cancer Molecular biology Related Article