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Caveolin-1 Is Down-Regulated in Human Lung Carcinoma and Acts as a Candidate Tumor Suppressor Gene* FREE TO VIEW

Martin M. Bélanger, MS; Élise Roussel, MS; Jacques Couet, PhD
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*From the Unité de Recherche en Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, Centre de Recherche Hôpital Laval, Sainte-Foy, QC, Canada.

Correspondence to: Jacques Couet, PhD, Unité de Recherche en Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, Centre de Recherche Hôpital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, QC, G1V 4G5 Canada; e-mail: jacques.couet@med.ulaval.ca

Chest. 2004;125(5_suppl):106S. doi:10.1378/chest.125.5_suppl.106S
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Caveolin-1 expression is down-regulated in oncogenically transformed fibroblasts as well as in breast and lung carcinoma cell lines. In the present study, we studied by immunohistochemistry the expression of caveolin-1 and caveolin-2 proteins in primary non-small cell lung tumors of human origin. All tumor specimens tested were negative for both caveolins in patients who had not undergone neoadjuvant therapy prior to surgery (32 of 32 patients). Both caveolin-1 and caveolin-2 were abundantly expressed in the tissue surrounding the tumors. Fibroblasts, alveolar epithelial cells, smooth muscle cells, and endothelial cells were all positive for caveolins. In order to better understand the potential effects on lung cancer cells of this caveolin induction, we expressed caveolin-1 complementary DNA in a lung adenocarcinoma cell line (Calu-6). In cancer cells overexpressing caveolin-1, proliferation was strongly reduced. We also observed a sharp decrease in cell motility after caveolin-1 expression in Calu-6 cells. However, no changes were observed in terms of sensitivity to cytotoxic drugs.

We also studied a subset of primary lung tumors from patients who were treated prior to surgery with various regimens of chemotherapy and/or radiotherapy. In this particular population, 50% of patients (7 of 14 patients) showed both caveolin-1 and caveolin-2 expression in their tumors. This caveolin expression was not related to tumor type, response to treatment, sex, or therapy regimen.

Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin-1 expression has been reported, suggesting a role for caveolin-1 in the acquisition and/or the maintenance of the multidrug resistance phenotype. In order to better understand the observation in human lung tumors, we treated drug-sensitive lung cancer cells (ie, A549, Calu-6, or NCI-H69 cells) with various cytotoxic drugs (ie, taxol, doxorubicin, or etoposide). Exposure to chemotherapeutic agents was sufficient to strongly up-regulate both caveolin-1 and caveolin-2 messenger RNA and protein levels. This up-regulation was sustained even a week after drug removal. The up-regulation of caveolin expression was dose-dependent. Our results suggest that caveolin-1 has tumor suppressor activity and is down-regulated during the development of lung cancer. Caveolin up-regulation is an early cellular response to a cytotoxic stress taking place well before drug resistance is manifested.

Supported by the Fondation J.D. Bégin and Le Réseau en Santé Respiratoire (RSR) du Fonds de la recherche en Santé du Québec.




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