Wei Yang1, Ming Cui1, Jungchieh Lee1, Wei Gong1, Song Wang1, Jingjing Fu1, Gongxiong Wu1, Kun Yan1. 1. 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing 100142, China ; 3 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China ; 4 Department of Cardiovascular and Neurovascular, Guangzhou Medical University, Guangzhou 510182, China ; 5 Department of Oncology, The first Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China.
Abstract
BACKGROUND: We investigated the effect of a small molecular inhibitor of heat shock protein (HSP), quercetin, on tumor radiofrequency (RF) ablation, and explored the underlying molecular mechanisms. METHODS: In in vivo study, rats with R3230 breast adenocarcinoma were sacrificed 24 h post-treatment and gross coagulation areas were compared, and next, randomized into four treatment arms (control, quercetin alone, RF alone, and combination) for Kaplan-Meier analysis of defined endpoint survival. Then the distribution and expression levels of heat shock protein 70 (HSP70), cleaved caspase-3 and heat shock factor 1 (HSF1) were analyzed after different treatments. In in vitro study, we used quercetin to promote SK-HEP-1 (hepatic) and MCF-7 (breast) cancer cell apoptosis in heat shock cell model, and siRNA was used to block c-Jun and to explore the role of activating protein-1 (AP-1) signaling pathways. RESULTS: We found the effects of quercetin plus RFA resulted in increase on the tumor destruction/endpoint survival (26.5±3.4 d) in vivo, compared with RF alone (17.6±2.5 d) and quercetin alone (15.7±3.1 d). Most importantly, quercetin-induced cancer cell death required the presence of HSF1 in animal model. Furthermore, quercetin directly down-regulated expression of HSF1 in vitro, which our findings have revealed, required the activation of AP-1 signaling pathways by loss-of-function analysis using siRNA mediated targeting of c-Jun. CONCLUSIONS: These results indicated a protective role of quercetin in tumor ablation and highlighted a novel mechanism involving HSP70 with HSF1 pathway in thermal ablation of solid tumors.
BACKGROUND: We investigated the effect of a small molecular inhibitor of heat shock protein (HSP), quercetin, on tumor radiofrequency (RF) ablation, and explored the underlying molecular mechanisms. METHODS: In in vivo study, rats with R3230 breast adenocarcinoma were sacrificed 24 h post-treatment and gross coagulation areas were compared, and next, randomized into four treatment arms (control, quercetin alone, RF alone, and combination) for Kaplan-Meier analysis of defined endpoint survival. Then the distribution and expression levels of heat shock protein 70 (HSP70), cleaved caspase-3 and heat shock factor 1 (HSF1) were analyzed after different treatments. In in vitro study, we used quercetin to promote SK-HEP-1 (hepatic) and MCF-7 (breast) cancer cell apoptosis in heat shock cell model, and siRNA was used to block c-Jun and to explore the role of activating protein-1 (AP-1) signaling pathways. RESULTS: We found the effects of quercetin plus RFA resulted in increase on the tumor destruction/endpoint survival (26.5±3.4 d) in vivo, compared with RF alone (17.6±2.5 d) and quercetin alone (15.7±3.1 d). Most importantly, quercetin-induced cancer cell death required the presence of HSF1 in animal model. Furthermore, quercetin directly down-regulated expression of HSF1 in vitro, which our findings have revealed, required the activation of AP-1 signaling pathways by loss-of-function analysis using siRNA mediated targeting of c-Jun. CONCLUSIONS: These results indicated a protective role of quercetin in tumor ablation and highlighted a novel mechanism involving HSP70 with HSF1 pathway in thermal ablation of solid tumors.
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