EMAIL THIS PAGE TO A FRIEND

Journal of virology

Chemical induction of unfolded protein response enhances cancer cell killing through lytic virus infection.


PMID 25187554

Abstract

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

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

05-599
Anti-E1A (Ad2/Ad5) Antibody, clone M73, 100 µg, Detect E1A (Ad2/Ad5) with Anti-E1A (Ad2/Ad5) Antibody, clone M73 (Mouse Monoclonal Antibody), that has been shown to work in IP, WB, ICC.
SAB1408009
Anti-PTGES2 antibody produced in mouse, purified immunoglobulin, buffered aqueous solution
HPA020631
Anti-PTGES2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
SAB1411453
Anti-PTGES2 antibody produced in rabbit, purified immunoglobulin, buffered aqueous solution
SAB3500381
Anti-XBP-1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
GW21291 Anti-XBP1 (ab1) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
GW22509 Anti-XBP1 (ab2) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
AV38552
Anti-XBP1 (AB2) antibody produced in rabbit, affinity isolated antibody
SAB1406598
Anti-XBP1 antibody produced in mouse, purified immunoglobulin, buffered aqueous solution
SAB2102720
Anti-XBP1 antibody produced in rabbit, affinity isolated antibody
HPA044305
Anti-XBP1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
WH0080142M1
Monoclonal Anti-PTGES2 antibody produced in mouse, clone 5B7, purified immunoglobulin, buffered aqueous solution
SAB3500473
Monoclonal Anti-XBP-1 antibody produced in mouse, clone 3H1G4, purified immunoglobulin, buffered aqueous solution
SAB3500474
Monoclonal Anti-XBP-1 antibody produced in mouse, clone 9B7E5, purified immunoglobulin, buffered aqueous solution
WH0007494M1
Monoclonal Anti-XBP1 antibody produced in mouse, clone 3F5, purified immunoglobulin, buffered aqueous solution
SAB1404531
Monoclonal Anti-XBP1 antibody produced in mouse, clone 2D9, purified immunoglobulin, buffered aqueous solution