Human papillomavirus 18 oncoproteins E6 and E7 enhance irradiation- and chemotherapeutic agent-induced apoptosis in p53 and Rb mutated cervical cancer cell lines

Tumor suppressor genes p53 and Rb are important in cell cycle control. Nece ssity of wild type p53 is implicated in irradiation-induced apoptosis. Nume rous tumor cells carry p53 mutations and yet are sensitive to irradiation o r chemotherapeutic agents. Therefore p53-and Rb-independent pathways must e xist to account for irradiation-induced apoptosis. We evaluated the apoptot ic response of a p53- and Rb-mutated. Human Papilloma Virus (HPV) negative cervical cancer cell line (C33a), and C33a cell lines infected with HPV 18 oncoproteins E6, E7, and E6&7 using recombinant retrovirus to various apopt osis-inducing agents including gamma irradiation, mitomycin C (MMC), and st aurosporine (SSP). Apoptosis was measured by avidinebiotin tunnel staining method. Our results showed significant apoptosis in C33a cell lines in resp onse to gamma-irradiation, MMC, and SSP. Moreover, apoptosis was enhanced w hen HPV 18E6, and E6&7 infected C33a cell lines were treated with irradiati on, MMC, and SSP. HPV 18 E7 infected C33a cell lines enhanced the apoptotic response to irradiation and to MMC, but not to SSP. In conclusion, our res ults imply the presence of a p53 and Rb-independent pathway in irradiation- induced apoptosis in cervical cancer cell lines; this effect is even more e vident in HPV oncoprotein infected cell lines. The radiosensitizing effects of HPV oncoproteins may lead to new perspectives in the treatment of cervi cal cancer.