Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus-Infected Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 11; pp. 4878 - 4884
• Main Authors: LANLAN WEI, GRAVITT, Patti E, HEBIN SONG, MALDONADO, Anastacia M, OZBUN, Michelle A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2009
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Biological and medical sciences; Cells, Cultured; Cervix Uteri - pathology; Cervix Uteri - virology; DNA Damage; Dose-Response Relationship, Drug; Epithelial Cells - drug effects; Epithelial Cells - virology; Female; Gene Expression Regulation, Viral - drug effects; Genes, Viral - drug effects; Genome, Viral - drug effects; Humans; Infectious diseases; Medical sciences; Mice; Mutation - drug effects; Nitric Oxide - pharmacology; Papillomavirus Infections - genetics; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; Pharmacology. Drug treatments; Retinoblastoma Protein - metabolism; Transcription, Genetic - drug effects; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation - drug effects; Viral diseases; Transcription; Papovaviridae; Infection; Papillomavirus; Virus; Human papillomavirus; Nitric oxide; Viral disease; Genetics; Early; Infected cell; Lesion; Mutation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-4695

High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.