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

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.