title: Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.
abstract: Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D and radiotherapy in melanoma cell lines with a BRAF mutant, Ras mutant or BRAF/Ras wild type genotype. The data indicates that RT3D combined with radiotherapy significantly increased cytotoxicity relative to either single agent, independent of genotype, both in vitro and in vivo. The mechanism of enhanced cytotoxicity was dependent on an increase in viral replication, mediated by CUG2 up-regulation and subsequent down-regulation of pPKR and p-eIF2α, leading to the activation of mitochondrial apoptotic signalling resulting in increased cell death.
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Gráinne
authors.initials: G
authors.lastname: McEntee
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Joan N
authors.initials: JN
authors.lastname: Kyula
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mansfield
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.|Sarcoma/Melanoma Unit, Department of Academic Surgery, Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Smith
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.|Sarcoma/Melanoma Unit, Department of Academic Surgery, Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilkinson
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Gregory
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Roulstone
authors.affiliation: Oncolytics Biotech Inc., Calgary, Canada.
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003131:Combined Modality Therapy / Q000379:methods; D015536:Down-Regulation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D012089:Mammalian orthoreovirus 3 / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D009154:Mutation; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction / Q000528:radiation effects*; D015854:Up-Regulation; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C534000:CENPW protein, human; D002868:Chromosomal Proteins, Non-Histone; D015852:Eukaryotic Initiation Factor-2; C482119:BRAF protein, human; C000602769:EIF2AK2 protein, human; D048493:Proto-Oncogene Proteins B-raf; D019892:eIF-2 Kinase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CUG2; apoptosis; melanoma; radiotherapy; reovirus