siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells.
The targeted inhibition of antiapoptotic factors in tumour cells may provide a rational approach towards the development of novel anticancer therapies. Using human papillomavirus (HPV)-transformed cells as a model system, we investigated if RNA interference (RNAi)-mediated gene silencing can be employed in order to overcome the apoptosis resistance of cancer cells. We found that both vector-borne and synthetic small interfering (si)RNAs, specifically directed against the antiapoptotic HPV E6 oncogene, restored dormant tumour suppressor pathways in HPV-positive cancer cells that are otherwise inactive in the presence of E6. This ultimately resulted in massive apoptotic cell death, selectively in HPV-positive tumour cells. These findings show that RNAi provides a powerful molecular strategy to inactivate intracellular E6 function efficiently. Moreover, they define E6 as a most promising therapeutic target to eliminate HPV-positive tumour cells specifically by RNAi. Thus, by sequence-specific targeting of antiapoptotic genes, siRNAs may be developed into novel therapeutics that can efficiently correct the apoptosis deficiency of cancer cells.
Butz
Karin
K
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg D-69120, Germany.
Ristriani
Tutik
T
Hengstermann
Arnd
A
Denk
Claudia
C
Scheffner
Martin
M
Hoppe-Seyler
Felix
F
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells / Q000187:drug effects / Q000821:virology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53