Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene.
Increased resistance to apoptosis is a hallmark of many tumor cells. The functional inhibition of specific antiapoptotic factors may provide a rational basis for the development of novel therapeutic strategies. We investigated here whether the RNA interference (RNAi) technology could be used to increase the apoptotic susceptibility of cancer cells. As a molecular target, we chose the antiapoptotic livin (ML-IAP, KIAP) gene, which is expressed in a subset of human tumors. We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression. Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFalpha. The effects were specific for Livin-expressing tumor cells. Our results (i) provide direct evidence that the intracellular interference with livin gene expression resensitizes human tumor cells to apoptosis, (ii) define the livin gene as a promising molecular target for therapeutic inhibition, and (iii) show that the livin gene is susceptible to efficient and specific silencing by the siRNA technology.
Crnkovic-Mertens
Irena
I
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg D-69120, Germany.
Hoppe-Seyler
Felix
F
Butz
Karin
K
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D002352:Carrier Proteins; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering