Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene

Oncogene. 2003 Nov 13;22(51):8330-6. doi: 10.1038/sj.onc.1206973.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis*
  • Base Sequence
  • Carrier Proteins / genetics*
  • Cell Line, Tumor
  • DNA Primers
  • Gene Silencing*
  • Humans
  • In Situ Nick-End Labeling
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins / genetics*
  • RNA, Small Interfering / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • BIRC7 protein, human
  • Carrier Proteins
  • DNA Primers
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering