Cellular responses of HPV-positive cancer cells to genotoxic anti-cancer agnets: Repression of E6/E7-oncogene expression and induction of apoptosis

Abstract

The E6 gene of tumor-associated types of human papillomaviruses codes for a functional antagonist of p53. Overexpression of E6 from heterologous promoters can block p53-mediated cellular responses to DNA damage, such as transcriptional stimulation of p53 target genes and cell-cycle arrest in G1. In contrast, genotoxic treatment of HPV-positive cancer cells, which express the E6 gene from chromosomally integrated viral copies, results in increased expression of the p53 target gene p21(WAF1) and, in several cell lines, induction of G1 arrest. In the present study, we show that treatment with genotoxic agents, such as mitomycin C and cisplatin, leads to strong repression of viral E6/E7 oncogene expression in HPV16- and HPV 18-positive cervical carcinoma cell lines. Kinetic analyses revealed that reduction of E6/E7 expression was not a prerequisite for induction of p21(WAF1). We furthermore found that the apoptosis promoting box gene could be induced by genotoxic stress in some, but not all, HPV-positive cancer cell lines. Treatment with DNA-damaging agents eventually resulted in apoptotic cell death of HPV-positive cancer cells, irrespective of their capacity to induce the p53 target gene box. These results support the notion that HPV-positive cancer cells can exhibit intact cellular responses to genotoxic stress, which may involve p53-dependent and -independent biochemical pathways. The ability of HPV-positive cancer cells to induce apoptotic cell death in response to DNA damage could provide a molecular explanation for the therapeutic effects of genotoxic agents in the treatment of cervical cancer.