title: Drug-induced caspase 8 upregulation sensitises cisplatin-resistant ovarian carcinoma cells to rhTRAIL-induced apoptosis.
abstract: BACKGROUND
  Drug resistance is a major problem in ovarian cancer. Triggering apoptosis using death ligands such as tumour necrosis factor-related apoptosis inducing ligand (TRAIL) might overcome chemoresistance.
  
  
  METHODS
  We investigated whether acquired cisplatin resistance affects sensitivity to recombinant human (rh) TRAIL alone or in combination with cisplatin in an ovarian cancer cell line model consisting of A2780 and its cisplatin-resistant subline CP70.
  
  
  RESULTS
  Combining cisplatin and rhTRAIL strongly enhanced apoptosis in both cell lines. CP70 expressed less caspase 8 protein, whereas mRNA levels were similar compared with A2780. Pre-exposure of particularly CP70 to cisplatin resulted in strongly elevated caspase 8 protein and mRNA levels. Caspase 8 mRNA turnover and protein stability in the presence or absence of cisplatin did not differ between both cell lines. Cisplatin-induced caspase 8 protein levels were essential for the rhTRAIL-sensitising effect as demonstrated using caspase 8 small-interfering RNA (siRNA) and caspase-8 overexpressing constructs. Cellular FLICE-inhibitory protein (c-FLIP) and p53 siRNA experiments showed that neither an altered caspase 8/c-FLIP ratio nor a p53-dependent increase in DR5 membrane expression following cisplatin were involved in rhTRAIL sensitisation.
  
  
  CONCLUSIONS
  Cisplatin enhances rhTRAIL-induced apoptosis in cisplatin-resistant ovarian cancer cells, and induction of caspase 8 protein expression is the key factor of rhTRAIL sensitisation.
authors.affiliation: Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: E W
authors.initials: EW
authors.lastname: Duiker
authors.forename: A
authors.initials: A
authors.lastname: Meijer
authors.forename: A R M
authors.initials: AR
authors.lastname: van der Bilt
authors.forename: G J
authors.initials: GJ
authors.lastname: Meersma
authors.forename: N
authors.initials: N
authors.lastname: Kooi
authors.forename: A G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: S
authors.initials: S
authors.lastname: de Jong
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053181:Caspase 8; D002945:Cisplatin