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.
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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 |
Journal | Neoplasia (New York, N.Y.)
(Neoplasia)
Vol. 19
Issue 10
Pg. 735-749
(Oct 2017)
ISSN: 1476-5586 [Electronic] United States |
PMID | 28843398
(Publication Type: Journal Article)
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Copyright | Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- E2F Transcription Factors
- Oncogene Proteins, Viral
- RNA, Small Interfering
- Tumor Suppressor Protein p53
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects, genetics)
- Cell Line, Tumor
- Cell Proliferation
(drug effects, genetics)
- Cell Tracking
- Disease Models, Animal
- E2F Transcription Factors
(genetics, metabolism)
- Gene Expression
- Gene Expression Regulation
(drug effects)
- Genes, Reporter
- Humans
- Mice
- Microscopy, Confocal
- Oncogene Proteins, Viral
(genetics)
- Papillomaviridae
(genetics)
- RNA Interference
- RNA, Small Interfering
- Signal Transduction
(drug effects)
- Tumor Suppressor Protein p53
(genetics, metabolism)
- Xenograft Model Antitumor Assays
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