title: Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53.
abstract: Survivin, a member of the inhibitors-of-apoptosis gene family, is overexpressed in many tumor types. Survivin is a prognostic marker of soft-tissue sarcomas, but the downregulation of survivin expression and the possible dependency of survivin downregulation on p53 in these tumors have not been investigated. Therefore, we applied small interfering RNA (siRNA) to knock down the expression of survivin in five human sarcoma cell lines with wild-type or mutant p53 alleles. Compared with survivin mRNA expression in the nonsense siRNA-treated sarcoma cell lines, expression after treatment with survivin-specific siRNA was reduced by 73-88%; survivin protein expression was reduced by 52-81%. This finding was coupled with a reduction in clonogenic survival ranging from 65-86%. However, less than 10% of cells treated with survivin-specific siRNA underwent apoptosis. Cell-cycle and morphologic analyses showed that after a dramatic increase in the number of treated cells in the G2/M phase, some of the cells became polyploid; this result indicates that mitosis of a substantial number of treated cells was incomplete. Our findings suggest that survivin-specific siRNA could be a selective treatment to kill sarcoma cells regardless of the presence or absence of wild-type p53 alleles.
authors.affiliation: Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle(S), Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kappler
authors.forename: Matthias
authors.initials: M
authors.lastname: Bache
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
authors.forename: Matthias
authors.initials: M
authors.lastname: Kotzsch
authors.forename: Matti
authors.initials: M
authors.lastname: Panian
authors.forename: Peter
authors.initials: P
authors.lastname: Würl
authors.forename: Karen
authors.initials: K
authors.lastname: Blümke
authors.forename: Hannelore
authors.initials: H
authors.lastname: Schmidt
authors.forename: Axel
authors.initials: A
authors.lastname: Meye
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002470:Cell Survival; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007120:Immunochemistry; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009363:Neoplasm Proteins; D011123:Polyploidy; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000077022:Survivin; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D016159:Tumor Suppressor Protein p53