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. Necessity of wild type p53 is implicated in irradiation-induced apoptosis. Numerous tumor cells carry p53 mutations and yet are sensitive to irradiation or chemotherapeutic agents. Therefore p53-and Rb-independent pathways must exist to account for irradiation-induced apoptosis. We evaluated the apoptotic 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 apoptosis-inducing agents including gamma irradiation, mitomycin C (MMC), and staurosporine (SSP). Apoptosis was measured by avidinebiotin tunnel staining method. Our results showed significant apoptosis in C33a cell lines in response to gamma-irradiation, MMC, and SSP. Moreover, apoptosis was enhanced when HPV 18 E6, and E6&7 infected C33a cell lines were treated with irradiation, 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 results imply the presence of a p53- and Rb-independent pathway in irradiation-induced apoptosis in cervical cancer cell lines: this effect is even more evident in HPV oncoprotein infected cell lines. The radiosensitizing effects of HPV oncoproteins may lead to new perspectives in the treatment of cervical cancer.
Department of Obstetrics and Gynecology, Georgetown University Medical Center, USA.
G
G
Kilic
M
M
Cardillo
M
M
Ozdemirli
B
B
Arun
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005260:Female; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016685:Mitomycin; D019311:Staurosporine