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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2007-11, Vol.67 (22), p.10910-10919
• Main Authors: MESLIN, Franck, HAMAÏ, Ahmed, GAO, Ping, JALIL, Abdelali, CAHUZAC, Nathalie, CHOUAIB, Salem, MEHRPOUR, Maryam
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Apoptosis; bcl-X Protein - metabolism; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Carcinoma - drug therapy; Carcinoma - pathology; Cell Death; Cell Line, Tumor; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Gene Silencing; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Prions - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-0512

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.