CELLULAR-RESPONSES OF HPV-POSITIVE CANCER-CELLS TO GENOTOXIC ANTICANCER AGENTS - REPRESSION OF E6 E7-ONCOGENE EXPRESSION AND INDUCTION OF APOPTOSIS/

The E6 gene of tumor-associated types of human papillomaviruses codes for a functional antagonist of p53. Overexpression of Eb from heterolo gous promoters can block p53-mediated cellular responses to DNA damage , such as transcriptional stimulation of p53 target genes and cell-cyc le arrest in G(1). In contrast, genotoxic treatment of HPV-positive ca ncer cells, which express the E6 gene from chromosomally integrated vi ral copies, results in increased expression of the p53 target gene p21 (WAF1) and, in several cell lines, induction of G(1) arrest. In the pr esent study, we show that treatment with genotoxic agents, such as mit omycin C and cisplatin, leads to strong repression of viral E6/E7 onco gene expression in HPV16- and HPV18-positive cervical carcinoma cell l ines. Kinetic analyses revealed that reduction of E6/E7 expression was not a prerequisite for induction of p21(WAF1). We furthermore found t hat the apoptosis-promoting box gene could be induced by genotoxic str ess in some, but not all, HPV-positive cancer cell lines. Treatment wi th DNA-damaging agents eventually resulted in apoptotic cell death of HPV-positive cancer cells, irrespective of their capacity to induce th e p53 target gene box. These results support the notion that HPV-posit ive cancer cells can exhibit intact cellular responses to genotoxic st ress, which may involve p53-dependent and -independent biochemical pat hways. The ability of HPV-positive cancer cells to induce apoptotic ce ll death in response to DNA damage could provide a molecular explanati on for the therapeutic effects of genotoxic agents in the treatment of cervical cancer. (C) 1996 Wiiey-Liss, Inc.