title: Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus.
abstract: Effective oncolytic virus (OV) therapy is dependent on the ability of replication-competent viruses to kill infected cancer cells. We previously showed that human pancreatic ductal adenocarcinoma (PDAC) cell lines are highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV), in part due to differences in type I interferon (IFN) signaling. Here, using 10 human PDAC cell lines and three different VSV recombinants (expressing ΔM51 or wild type matrix protein), we examined cellular and viral factors affecting VSV-mediated apoptosis activation in PDACs. In most cell lines, VSVs activated both extrinsic and intrinsic apoptosis pathways, and VSV-ΔM51 primarily activated the type II extrinsic pathway. In cells with defective IFN signaling, all VSV recombinants induced robust apoptosis, whereas VSV-ΔM51 was a more effective apoptosis activator in PDACs with virus-inducible IFN signaling. Three cell lines constitutively expressing high levels of IFN-stimulated genes (ISGs) were resistant to apoptosis under most experimental conditions, even when VSV replication levels were dramatically increased by Jak inhibitor I treatment. Two of these cell lines also poorly activated apoptosis when treated with Fas activating antibody, suggesting a general defect in apoptosis.
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Felt
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Moerdyk-Schauwecker
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA. Electronic address: vzgrdzel@uncc.edu.
authors.forename: Valery Z
authors.initials: VZ
authors.lastname: Grdzelishvili
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D006801:Humans; D007370:Interferon Type I / Q000502:physiology; D009154:Mutation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000502:physiology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; C094460:M protein, Vesicular stomatitis virus; D014763:Viral Matrix Proteins
keywords: Apoptosis; M51 mutant; Matrix protein; Mononegavirales; Non-segmented negative-strand virus; Oncolytic virus; Pancreatic cancer; Rhabdovirus; VSV; Vesicular stomatitis virus