title: Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells.
abstract: Oncolytic human herpes simplex virus type 1 (HSV-1) shows promising treatment efficacy in late-stage clinical trials. The anticancer activity of oncolytic viruses relies on deregulated pathways in cancer cells, which make them permissive to oncolysis. To identify pathways that restrict HSV-1 KM100-mediated oncolysis, this study used a pooled genome-wide short hairpin RNA library and found that depletion of the splicing factor arginine-rich splicing factor 2 (SRSF2) leads to enhanced cytotoxicity of breast cancer cells by KM100. Serine/arginine-rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing. Further characterization showed that KM100 infection of HS578T cells under conditions of low SRSF2 leads to pronounced apoptosis without a corresponding increase in virus replication. As DNA topoisomerase I inhibitors can limit the phosphorylation of SRSF2, we combined a topoisomerase I inhibitor chemotherapeutic with KM100 and observed synergistic anticancer effect in vitro and prolonged survival of tumor-bearing mice in vivo.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: S T
authors.initials: ST
authors.lastname: Workenhe
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Ketela
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: B P
authors.initials: BP
authors.lastname: Cuddington
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D055786:Gene Knockout Techniques; D023281:Genomics; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D000077146:Irinotecan; D016086:Lentivirus / Q000235:genetics*; D050130:Oncolytic Virotherapy; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D000077146:Irinotecan; D002166:Camptothecin