Silencing of prion protein sensitizes breast adriamycin-resistant carcinoma cells to TRAIL-mediated cell death

Cancer Res. 2007 Nov 15;67(22):10910-9. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • Carcinoma / drug therapy*
  • Carcinoma / pathology*
  • Cell Death
  • Cell Line, Tumor
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Gene Silencing
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Prions / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • bcl-X Protein / metabolism


  • Antibiotics, Antineoplastic
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Prions
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • bcl-X Protein
  • Doxorubicin