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Prion Protein Prevents Human Breast Carcinoma Cell Line from Tumor Necrosis Factor -Induced Cell Death

¹ Laboratoire de Cytokines et Immunologie des Tumeurs Humaines, Institut National de la Santé et de la Recherche Médicale U-487, Institut Gustave Roussy Pavillon de Recherche 1 and Institut Fédératif de Recherche, Villejuif, France;
² Unité Mixte de Recherche 1161 de Virologie Institut National de Recherche Agronomique Agence Française de Sécurité Sanitaire des Aliments École National Vétérinaire d’Alfort, Maisons Alfort, France;
³ Commisariat à l’Énergie Atomique, Service de Génomique Fonctionnelle, Evry, France;
⁴ Unité Mixte de Recherche 8125 Centre National de la Recherche Scientifique, Institut Gustave Roussy Pavillon de Recherche 2, Villejuif, France; and
⁵ Commisariat à l’Énergie Atomique, Service de Neurovirologie, Centre de Recherche du Service Santé des Armés, École Pratique des Hautes Études, Institut Paris sud sur les Cytokines, Université Paris XI, Fontenay-aux-Roses, France

To define genetic determinants of tumor cell resistance to the cytotoxic action of tumor necrosis factor (TNF), we have applied cDNA microarrays to a human breast carcinoma TNF-sensitive MCF7 cell line and its established TNF-resistant clone. Of a total of 5760 samples of cDNA examined, 3.6% were found to be differentially expressed in TNF-resistant 1001 cells as compared with TNF-sensitive MCF7 cells. On the basis of available literature data, the striking finding is the association of some differentially expressed genes involved in the phosphatidylinositol-3-kinase/Akt signaling pathway. More notably, we found that the PRNP gene coding for the cellular prion protein (PrP^c), was 17-fold overexpressed in the 1001 cell line as compared with the MCF7 cell line. This differential expression was confirmed at the cell surface by immunostaining that indicated that PrP^c is overexpressed at both mRNA and protein levels in the TNF-resistant derivative. Using recombinant adenoviruses expressing the human PrP^c, our data demonstrate that PrP^c overexpression converted TNF-sensitive MCF7 cells into TNF-resistant cells, at least in part, by a mechanism involving alteration of cytochrome c release from mitochondria and nuclear condensation.

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