Millepachine, a potential topoisomerase II inhibitor induces apoptosis via activation of NF-κB pathway in ovarian cancer
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Wenshuang Wu1,2,*, Buyun Ma3,*, Haoyu Ye1, Taijin Wang1, Xiaoyan Wang1, Jianhong Yang1, Yuquan Wei1, Jingqiang Zhu2, Lijuan Chen1
1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China
2Department of Thyroid and Breast Surgery, West China Hospital of Sichuan University, Chengdu, China
3Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, China
*These authors contributed equally to the work
Keywords: topoisomerase II inhibitor, millepachine, apoptosis, NF-κB pathway, ovarian cancer
Received: January 08, 2016 Accepted: June 16, 2016 Published: July 20, 2016
Millepachine (MIL) was a novel chalcone that was separated from Millettia pachycarpa Benth (Leguminosae). We found MIL induced apoptosis through activating NF-κB pathway both in SK-OV-3 and A2780S cells. Western blot showed that MIL increased the levels of IKKα, p-IKKα/β, p-IκBα and NF-κB (p65) proteins, and decreased the expression of IκBα protein. Immunohistochemistry analysis indicated that translocation of NF-κB into the nucleus increased in both ovarian cancer cells. EMSA assay proved MIL enhanced NF-κB DNA-binding activity in the nuclear. That specific NF-κB inhibitors alleviated MIL-induced apoptosis suggested NF-κB activation showed a pro-apoptotic function in SK-OV-3 and A2780S cells. Since NF-κB could be activated by double strand breaks and showed a pro-apoptotic function in the DNA damage response, SCGE assay and western blot revealed that MIL caused DNA strand breaks and significantly increased the level of p-ATM protein and further increased the levels of p-IKKα/β and NF-κB (p65) protein in SK-OV-3 and A2780S cells, while a specific ATM inhibitor could alleviated these effects. Moreover, Topoisomerase II drug screening kit and computer modeling assay were used to prove that MIL induced the production of linear DNA and inhibited the activity of topoisomerase II through binding with Topoisomerase II-Cleaved DNA complex to stabilize the complex. Taken together, our results identified that MIL exhibited anti-tumor activity through inhibiting topoisomerase II activity to induce tumor cells DNA damage, and MIL-activated NF-κB pathway showed a pro-apoptotic function in response to DNA damage.
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