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.