Chemical Induction of Unfolded Protein Response Enhances Cancer Cell Killing through Lytic Virus Infection

• DOI: 10.1128/jvi.02156-14
• Publication Date: 2014-09-04T17:34:18Z
• Authors: Vibhu Prasad; Maarit Suomalainen; Mirjam Pennauer; Artur Yakimovich; Vardan Andriasyan; Silvio Hemmi; Urs F. Greber
• Keywords: 0301 basic medicine; 2403 Immunology; Melanocytes / virology; 1109 Insect Science; Cell Death; Epithelial Cells / physiology; 2404 Microbiology; Epithelial Cells; Epithelial Cells / virology; 10124 Institute of Molecular Life Sciences; Oncolytic Viruses / growth & development; 3. Good health; Oncolytic Viruses; 03 medical and health sciences; Cell Line, Tumor; 2406 Virology; Unfolded Protein Response; 570 Life sciences; biology; Melanocytes / physiology; Humans; Melanocytes

ABSTRACT Cancer cells are susceptible to oncolytic viruses, albeit variably. Human adenoviruses (HAdVs) widely used agents that have been engineered produce progeny within the tumor and elicit bystander effects. We searched for host factors enhancing effects conducted a targeted RNA interference screen against guanine nucleotide exchange (GEFs) of small GTPases. show unfolded protein response (UPR), which is readily inducible in aggressive cells, enhances melanoma or epithelial cancer cell killing upon HAdV infection. UPR was triggered by knockdown Golgi-specific brefeldin A-resistant factor 1 (GBF-1) GBF-1 inhibitor golgicide A (GCA) stimulated GEF ADP ribosylation (Arfs) regulating endoplasmic reticulum (ER)-to-Golgi apparatus intra-Golgi membrane transport. Cells treated with GCA enhanced HAdV-induced cytopathic but not normal if drug applied several hours prior inoculation. This shown real-time label-free impedance measurements using xCELLigence system. GCA-treated contained fewer incoming HAdVs than control treatment boosted titers spreading cells. viral gene expression transgene from cytomegalovirus promoter B- C-species did enhance early region 1A (E1A) uninfected lines transfected plasmid reporter DNA. The UPR-enhanced required nuclease activity sensor inositol-requiring enzyme (IRE-1) X box binding (XBP-1), alleviate ER stress. collective results chemical induction viruses boost efficacy. IMPORTANCE difficult combat. wide range promise yet efficacy low. adenovirus found inhibition infection triggering IRE-1/XBP-1 branch (UPR). promote survival levels adenoviral immediate product E1A, virus spreading, Aggressive depend on and, hence, present prime targets combined strategy involving chemicals inducing UPR.