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Effect of HPV E6/E7 siRNA with Chemotherapeutic Agents on the Regulation of TP53/E2F Dynamic Behavior for Cell Fate Decisions

Authors :
Nirmal Rajasekaran
Hun Soon Jung
Soo Hyeon Bae
Chaithanya Chelakkot
Sungyoul Hong
Jong-Sun Choi
Dong-Seok Yim
Yu-Kyoung Oh
Yoon-La Choi
Young Kee Shin
Source :
Neoplasia: An International Journal for Oncology Research, Vol 19, Iss 10, Pp 735-749 (2017)
Publication Year :
2017
Publisher :
Elsevier, 2017.

Abstract

Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo. Compared to the E6/E7 SP alone, E6/E7 SP with cisplatin treatment effectively restored TP53 and RB/E2F signaling and contributes to differences in cell fate, such as apoptosis or cell cycle arrest. We also developed a cellular dynamics model that includes TP53-RB/E2F dynamics and cell proliferation profiles, and confirmed its utility for investigating E6/E7 siRNA-based combination regimens. Using a dual reporter system, we further confirmed the cross talk between TP53 and RB/E2F signaling mechanisms. Treatment of E6/E7 SP cationic liposome (i.v.) with cisplatin and paclitaxel (i.p.) potentially inhibited tumor growth in BALB/c-nude mice. Altogether, our findings suggest that stabilization of TP53 and the RB/E2F repressor complex by E6/E7 SP combined with low-dose chemotherapy can effectively suppress tumor growth.

Details

Language :
English
ISSN :
14765586 and 15228002
Volume :
19
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Neoplasia: An International Journal for Oncology Research
Publication Type :
Academic Journal
Accession number :
edsdoj.2fa6c0b77124668958555288e269051
Document Type :
article
Full Text :
https://doi.org/10.1016/j.neo.2017.07.005