title: TRAIL and Noxa are selectively upregulated in prostate cancer cells downstream of the RIG-I/MAVS signaling pathway by nonreplicating Sendai virus particles.
abstract: OBJECTIVE
  The treatment of cancer with oncolytic viruses primarily depends on the selective viral replication in cancer cells. However, a replication-incompetent hemagglutinating virus of Japan (HVJ; Sendai virus) envelope (HVJ-E) suppresses the growth of human cancer cells as effectively as replication-competent live HVJ without producing toxic effects in nonmalignant cells. Here, we analyze the molecular mechanism of the oncolytic activity of HVJ-E.
  
  
  METHODS
  The molecules responsible for HVJ-E-induced cancer cell death were elucidated in prostate cancer cell lines, and the effect of HVJ-E on orthotopic prostate cancers was evaluated in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice.
  
  
  RESULTS
  The liposome-mediated transfer of viral RNA genome fragments from HVJ-E suppressed the viability of prostate cancer cells but not the viability of the noncancerous prostate epithelium. Knockdown experiments using siRNAs showed that the cancer cell-selective killing induced by HVJ-E was mediated by retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). Downstream of the RIG-I/MAVS pathway, both TNF-related apoptosis-inducing ligand (TRAIL) and Noxa were upregulated by HVJ-E in the castration-resistant prostate cancer cell line PC3 but not in the noncancerous prostate epithelial cell line PNT2. TRAIL siRNA but not Noxa siRNA significantly inhibited HVJ-E-induced cell death in PC3 cells. However, Noxa siRNA effectively suppressed HVJ-E-induced cell death in DU145 cells, another castration-resistant prostate cancer cell line, in which Noxa but not TRAIL was upregulated by HVJ-E. Furthermore, the orthotopic prostate cancers were dramatically eradicated in immunodeficient mice injected with HVJ-E.
  
  
  CONCLUSIONS
  The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy.
authors.affiliation: Division of Gene Therapy Science, Departments of Urology and Pediatric Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Matsushima-Miyagi
authors.forename: Koji
authors.initials: K
authors.lastname: Hatano
authors.forename: Motonari
authors.initials: M
authors.lastname: Nomura
authors.forename: Liu
authors.initials: L
authors.lastname: Li-Wen
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Kotaro
authors.initials: K
authors.lastname: Saga
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimbo
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D016679:Genome, Viral; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050504:Oncolytic Viruses / Q000502:physiology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D015854:Up-Regulation; D014771:Virion / Q000502:physiology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012367:RNA, Viral; D011971:Receptors, Immunologic; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases