title: Knockdown of MADD and c-FLIP overcomes resistance to TRAIL-induced apoptosis in ovarian cancer cells.
abstract: OBJECTIVE
  The clinical utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the treatment of established human malignancies is limited by the development of resistance to TRAIL. We hypothesized that knockdown of map-kinase activating death domain containing protein (MADD), a TRAIL-resistance factor, may overcome TRAIL resistance in ovarian cancer cells.
  
  
  METHODS
  MADD expression in resected ovarian cancer specimens and cell lines was quantified with the use of polymerase chain reaction. Sensitivity of ovarian cancer cell lines to TRAIL, with or without MADD knockdown, was assessed.
  
  
  RESULTS
  MADD is expressed at relatively higher levels in human malignant ovarian cancer tissues and cell lines, compared with normal ovarian tissues. The cell lines OVCA429 and OVCAR3 were susceptible, and cell lines CAOV-3 and SKOV-3 were resistant to TRAIL. MADD knockdown in CAOV-3 cells, but not in SKOV-3 cells, conferred TRAIL sensitivity. Knockdown of cellular Fas-associated death domain-like interleukin-1 beta-converting enzyme-inhibitory protein (c-FLIP) in SKOV-3 cells increased spontaneous and TRAIL-induced apoptosis, which was further increased on MADD knockdown.
  
  
  CONCLUSIONS
  MADD/c-FLIP(L) knockdown can render TRAIL-resistant ovarian cancer cells susceptible to TRAIL.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Liang-Cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Shankar
authors.initials: S
authors.lastname: Jayaram
authors.forename: Lakshmy
authors.initials: L
authors.lastname: Ganesh
authors.forename: Lixia
authors.initials: L
authors.lastname: Qian
authors.forename: Jacob
authors.initials: J
authors.lastname: Rotmensch
authors.forename: Ajay V
authors.initials: AV
authors.lastname: Maker
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000502:physiology*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000502:physiology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand