BACKGROUND: Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors. In cancer cells, its expression is enhanced as a consequence of oncogenic signaling. We investigated the potential of a novel, peptide-based survivin inhibitor in breast cancer (SK-BR-3, MDA-MB-468) and glioblastoma (Tu9648) cells. These cells express high levels of survivin. MATERIALS AND METHODS: We downregulated survivin expression in tumor cells with a lentiviral gene transfer vector encoding a specific shRNA and a recombinant fusion protein, rSip, comprising the FTH1-derived survivin interaction domain, the human thioredoxin and a protein transduction domain. RESULTS: Downregulation of survivin expression decreased the growth and viability of tumor cells in culture and reduced growth of the cancer cells upon transplantation into immunodeficient mice. rSip selectively targets the anti-apoptotic function of survivin and causes tumor cell death. Non-transformed NIH/3T3 and MCF10A cells remain unaffected. CONCLUSIONS: rSip provides a lead structure for the development of drugs targeting the tumor cell "addiction protein" survivin.
BACKGROUND: Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors. In cancer cells, its expression is enhanced as a consequence of oncogenic signaling. We investigated the potential of a novel, peptide-based survivin inhibitor in breast cancer (SK-BR-3, MDA-MB-468) and glioblastoma (Tu9648) cells. These cells express high levels of survivin. MATERIALS AND METHODS: We downregulated survivin expression in tumor cells with a lentiviral gene transfer vector encoding a specific shRNA and a recombinant fusion protein, rSip, comprising the FTH1-derived survivin interaction domain, the humanthioredoxin and a protein transduction domain. RESULTS: Downregulation of survivin expression decreased the growth and viability of tumor cells in culture and reduced growth of the cancer cells upon transplantation into immunodeficientmice. rSip selectively targets the anti-apoptotic function of survivin and causes tumor cell death. Non-transformed NIH/3T3 and MCF10A cells remain unaffected. CONCLUSIONS: rSip provides a lead structure for the development of drugs targeting the tumor cell "addiction protein" survivin.
Authors: Regina Cencic; David R Hall; Francis Robert; Yuhong Du; Jaeki Min; Lian Li; Min Qui; Iestyn Lewis; Serdar Kurtkaya; Ray Dingledine; Haian Fu; Dima Kozakov; Sandor Vajda; Jerry Pelletier Journal: Proc Natl Acad Sci U S A Date: 2010-12-29 Impact factor: 11.205
Authors: A Islam; H Kageyama; N Takada; T Kawamoto; H Takayasu; E Isogai; M Ohira; K Hashizume; H Kobayashi; Y Kaneko; A Nakagawara Journal: Oncogene Date: 2000-02-03 Impact factor: 9.867
Authors: Gerald C Wallace; Yaenette N Dixon-Mah; W Alex Vandergrift; Swapan K Ray; Catherine P Haar; Amber M Mittendorf; Sunil J Patel; Naren L Banik; Pierre Giglio; Arabinda Das Journal: Metab Brain Dis Date: 2013-04-02 Impact factor: 3.584
Authors: Jacques A J Malherbe; Kathryn A Fuller; Bob Mirzai; Simon Kavanagh; Chi-Chiu So; Ho-Wan Ip; Belinda B Guo; Cecily Forsyth; Rebecca Howman; Wendy N Erber Journal: J Clin Pathol Date: 2016-04-08 Impact factor: 3.411