title: Silencing survivin splice variant 2B leads to antitumor activity in taxane--resistant ovarian cancer.
abstract: OBJECTIVE
  To study the role of survivin and its splice variants in taxane-resistant ovarian cancer.
  
  
  METHODS
  We assessed the mRNA levels of survivin splice variants in ovarian cancer cell lines and ovarian tumor samples. siRNAs targeting survivin were designed to silence all survivin splice variants (T-siRNA) or survivin 2B (2B-siRNA) in vitro and orthotopic murine models of ovarian cancer. The mechanism of cell death was studied in taxane-resistant ovarian cancer cells and in tumor sections obtained from different mouse tumors.
  
  
  RESULTS
  Taxane-resistant ovarian cancer cells express higher survivin mRNA levels than their taxane-sensitive counterparts. Survivin 2B expression was significantly higher in taxane-resistant compared with -sensitive cells. Silencing survivin 2B induced growth inhibitory effects similar to silencing total survivin in vitro. In addition, survivin 2B-siRNA incorporated into DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) nanoliposomes resulted in significant reduction in tumor growth (P < 0.05) in orthotopic murine models of ovarian cancer, and these effects were similar to T-siRNA-DOPC. The antitumor effects were further enhanced in combination with docetaxel chemotherapy (P < 0.01). Finally, we found a significant association between survivin 2B expression and progression-free survival in 117 epithelial ovarian cancers obtained at primary debulking surgery.
  
  
  CONCLUSIONS
  These data identify survivin 2B as an important target in ovarian cancer and provide a translational path forward for developing new therapies against this target.
authors.affiliation: University of Puerto Rico Comprehensive Cancer Center; Department of Biochemistry, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Vivas-Mejia
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Fatma
authors.initials: F
authors.lastname: Valiyeva
authors.forename: Mineko
authors.initials: M
authors.lastname: Shibayama
authors.forename: Arturo
authors.initials: A
authors.lastname: Chavez-Reyes
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000818:Animals; D017209:Apoptosis; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology*
chemical_list: C107489:BIRC5 protein, human; D001952:Bridged-Ring Compounds; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D043823:Taxoids; C080625:taxane