The HPV16 E6/E7 oncogene sensitizes human ovarian surface epithelial cells to low-dose but not high-dose 5-FU and 5-FUdR.
To evaluate the effect of HPV16 E6/E7 on drug sensitivity, primary human OSE cells were infected with HPV16 E6/E7 expressing retrovirus and then exposed to chemotherapeutic agents. Apoptosis induced by mitomycin C was dose-dependent in both primary OSE and E6E7/OSE cells. E6E7/OSE cells were more sensitive to mitomycin C than parental OSE cells. HPV16 E6/E7 also sensitized OSE cells to 5-FU and its derivative 5-FUdR, but only at low doses. This phenomenon was also observed in cervical cancer cells and was independent of thymidylate synthase, a target of thymine and thymidine analogues. We conclude that HPV16 E6/E7 specifically modulates the activity of 5-FU and 5-FUdR, and confers OSE cells hypersensitivity to low-dose but not high-dose 5-FU and 5-FUdR. Molecular analysis indicates that induction of p53 and p21, and suppression of pRB are associated with apoptosis induced by 5-FUdR and may partly explain the hypersensitivity of E6E7/OSE cells to low-dose 5-FUdR.
Hsu
Lih-Ching
LC
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. rsilh@mwri.magee.edu
Lee
Ray M
RM
White
Raymond L
RL
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage*; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
C118860:E6 protein, Human papillomavirus type 6; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D005467:Floxuridine; D013940:Thymidylate Synthase; D005472:Fluorouracil