Diffusible VP22-E2 protein kills bystander cells and offers a route for cervical cancer gene therapy.
Human papillomaviruses (HPVs) are a causative agent of cervical cancer and are implicated in several other types of malignant disease including cancer of the vulva, oral cancer, and skin cancer. In HPV-transformed cells, expression of the viral E6 and E7 oncogenes increases cell proliferation and inhibits apoptosis. Expression of the viral E2 protein in HPV-transformed cells represses transcription of E6 and E7 and induces apoptosis and/or growth arrest. We have shown previously that herpes simplex virus type 1 (HSV-1) VP22-HPV E2 fusion proteins can traffic between cells and induce apoptosis. Here we show that replication-defective adenoviruses can be used to deliver VP22-E2 fusion proteins to target cells. We show that the use of adenoviral vectors to deliver VP22-E2 proteins leads to high levels of apoptosis. Interestingly, VP22-E2 proteins produced in adenovirus-infected cells are able to enter uninfected cells and induce apoptosis. Trafficking between cells and the induction of apoptosis in bystander cells are detectable in a three-dimensional tumor model. These results suggest that adenoviral vectors expressing VP22-E2 fusion proteins could be used to treat cervical cancer and other HPV-associated diseases.
Green
Katie L
KL
Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Southgate
Tom D
TD
Mulryan
Kate
K
Fairbairn
Lez J
LJ
Stern
Peter L
PL
Gaston
Kevin
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D024201:Bystander Effect; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D004058:Diffusion; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D006367:HeLa Cells / Q000821:virology; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000628:therapy*; D015678:Viral Structural Proteins / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000235:genetics
D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; C076036:oncogene protein E2, Human papillomavirus type 1