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.
IMPORTANCE:
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.