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.

Document type:	Journal Article
Collections:	Excellence in Research Australia (ERA) - Collection UQ Diamantina Institute Publications

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
Sub-type	Article
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