Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus

• Published in: Virology (New York, N.Y.) N.Y.), 2015-01, Vol.474, p.163-173
• Main Authors: Felt, Sébastien A, Moerdyk-Schauwecker, Megan J, Grdzelishvili, Valery Z
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - therapy; Cell Line, Tumor; Humans; Infectious Disease; Interferon Type I - physiology; M51 mutant; Matrix protein; Mononegavirales; Mutation; Non-segmented negative-strand virus; Oncolytic Virotherapy; Oncolytic virus; Oncolytic Viruses - genetics; Oncolytic Viruses - physiology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Recombination, Genetic; Rhabdovirus; Signal Transduction - genetics; Vesicular stomatitis Indiana virus - genetics; Vesicular stomatitis Indiana virus - physiology; Vesicular stomatitis virus; Viral Matrix Proteins - genetics; Viral Matrix Proteins - physiology; Virus Replication; VSV
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2014.10.026

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.