A cancer cell-specific inducer of apoptosis

Green, Katie L.; Brown, Craig; Roeder, Geraldine E.; Southgate, Thomas D.; Gaston, Kevin

Abstract

Human papillomavirus (HPV) DNA is found in virtually all cervical cancers, strongly suggesting that these viruses are necessary to initiate this disease. The HPV E2 protein is required for viral replication, but E2 expression is usually lost in HPV-transformed cells because of the integration of viral DNA into the host chromosome. Several studies have shown that the reintroduction of E2 into HPV-transformed cells can induce growth arrest and apoptotic cell death. This raises the possibility that E2 could be useful in the treatment of HPV-induced disease. However, the effects of E2 on cell proliferation are not limited to HPV-transformed cells. The E2 protein from HPV type 16 can induce apoptosis via at least two pathways. One pathway involves the binding of E2 to p53 and operates in HPV-transformed cells, many non-HPV-transformed cell lines, and untransformed normal cells. The second pathway requires the binding of E2 to the viral genome and operates only in HPV-transformed cells. A mutation in E2 that significantly reduces the binding of this protein to p53 abrogates the induction of apoptosis in non-HPV-transformed cells and normal cells, but has no effect on the ability of the mutated protein to induce apoptosis in HPV-transformed cells. Here we show that a chimeric protein consisting of this mutant of E2, fused to the herpes simplex virus type 1 VP22 protein, can traffic between cells in a three-dimensional tumor model and induce apoptosis in HPV-transformed cells with high specificity. This cancer cell-specific inducer of apoptosis may be useful in the treatment of cervical cancer and other HPV-induced diseases.

Citation

Green, K. L., Brown, C., Roeder, G. E., Southgate, T. D., & Gaston, K. (2007). A cancer cell-specific inducer of apoptosis. Human Gene Therapy, 18(6), 547-561. doi:10.1089/hum.2006.042

• Journal Article Type: Article
• Acceptance Date: May 2, 2007
• Publication Date: 2007-06
• Deposit Date: Nov 1, 2018
• Journal: Human Gene Therapy
• Print ISSN: 1043-0342
• Publisher: Mary Ann Liebert
• Peer Reviewed: Peer Reviewed
• Volume: 18
• Issue: 6
• Pages: 547-561
• DOI: https://doi.org/10.1089/hum.2006.042
• Public URL: https://nottingham-repository.worktribe.com/output/1037711
• Publisher URL: https://www.liebertpub.com/doi/10.1089/hum.2006.042