 |
RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin
Putral, L. N., Bywater, M. J., Gu, W. Y., Saunders, N. A., Gabrielli, B. G., Leggatt, G. R. and McMillan, N. A. J. (2005) RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin. Molecular Pharmacology, 68 5: 1311-1319.
|
|
|
| Author(s) |
Putral, L. N.
Bywater, M. J.
Gu, W. Y.
Saunders, N. A.
Gabrielli, B. G.
Leggatt, G. R.
McMillan, N. A. J.
|
| Title |
RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin
|
| Journal name |
Molecular Pharmacology
|
| Publication date |
2005
|
| Volume number |
68
|
| Issue number |
5
|
| ISSN |
0026-895X
|
| Start page |
1311
|
| End page |
1319
|
| Total pages |
9
|
| Place of publication |
Bethesda
|
| Publisher |
American Society Pharmacology and Experimental Therapeutics
|
| Collection year |
2005
|
| Language |
eng
|
| Subject |
C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
|
| Abstract |
Targeted inhibition of oncogenes in tumor cells is a rational approach toward the development of cancer therapies based on RNA interference (RNAi). Tumors caused by human papillomavirus (HPV) infection are an ideal model system for RNAi-based cancer therapies because the oncogenes that cause cervical cancer, E6 and E7, are expressed only in cancerous cells. We investigated whether targeting HPV E6 and E7 oncogenes yields cancer cells more sensitive to chemotherapy by cisplatin, the chemotherapeutic agent currently used for the treatment of advanced cervical cancer. We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway. The loss of E6 and E7 resulted in a reduction in cellular viability concurrent with the induction of cellular senescence. Interference was specific in that no effect on HPV-negative cells was observed. We demonstrate that RNAi against E6 and E7 oncogenes enhances the chemotherapeutic effect of cisplatin in HeLa cells. The IC50 for HeLa cells treated with cisplatin was 9.4 mu M, but after the addition of a lentivirus-delivered shRNA against E6, the IC50 was reduced almost 4-fold to 2.4 mu M. We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone. Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels.
|
| Keyword(s) |
Pharmacology & Pharmacy
Carcinoma Cells
Messenger-rna
Breast-cancer
E7 Protein
P53 Status
In-vivo
E6
Senescence
Type-16
Gene
|
|
|
