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Silencing of Prion Protein Sensitizes Breast Adriamycin-Resistant Carcinoma Cells to TRAIL-Mediated Cell Death

¹ INSERM U753, Laboratoire d'Immunologie des Tumeurs Humaines, Interaction Effecteurs Cytotoxiques-Système Tumoral, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France and ² Chinese Academy of Sciences, Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Beijing, China

Requests for reprints: Maryam Mehrpour, INSERM U753, Laboratoire d'Immunologie des Tumeurs Humaines, Institut Gustave Roussy, PR1, F-94805 Villejuif Cedex, France. Phone: 33-14211-4852; Fax: 33-14211-5288; E-mail: mehrpour{at}igr.fr or mehrpour{at}ioz.ac.cn.

We investigated the relationship between the resistance to the proapoptotic action of tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and cellular prion protein (PrPc) function, using the TRAIL-sensitive MCF-7 human breast adenocarcinoma cell line and two TRAIL-resistant sublines: 2101 and MCF-7/ADR. All of the cell lines tested expressed TRAIL-R1 and TRAIL-R2. TRAIL decoy receptors were not detected, suggesting that the resistance of 2101 and MCF-7/ADR cells, strongly expressing PrPc, to TRAIL-mediated cell death was independent from the expression of TRAIL receptors and death-inducing signaling complex formation. Down-regulation of PrPc by small interfering RNA increased the sensitivity of Adriamycin- and TRAIL-resistant cells to TRAIL, but not to epirubicin/Adriamycin. TRAIL-mediated apoptosis in PrPc knocked-down cells was associated with caspase processing, Bid cleavage, and Mcl-1 degradation. In addition, an increased sensitivity of apoptosis-resistant cells to TRAIL after PrPc silencing was not associated with the increased recruitment of receptors and intracellular signaling molecule to the death-inducing signaling complex. Bcl-2 expression was substantially decreased after PrPc knock-down but the levels of Bcl-X_L and Mcl-1 were not affected. The down-regulation of Bcl-2 was concomitant with Bax delocalization. Our findings support the notion that silencing of PrPc facilitates the activation of proapoptotic Bax by down-regulation of Bcl-2 expression, thereby abolishing the resistance of breast cancer cells to TRAIL-induced apoptosis. [Cancer Res 2007;67(22):10910–9]