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Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways

2016; Impact Journals LLC; Volume: 7; Issue: 11 Linguagem: Inglês

10.18632/oncotarget.7276

1949-2553

Yingmin Wu, Zhuojia Chen, Guanmin Jiang, Kun-Shui Zhang, Qiao Liu, Shuwei Liang, Yan Zhou, Hongbin Huang, Jun Du, Hongsheng Wang,

Cytokine Signaling Pathways and Interactions

// Ying-Min Wu 1, * , Zhuo-Jia Chen 2, * , Guan-Min Jiang 3 , Kun-Shui Zhang 4 , Qiao Liu 1 , Shu-Wei Liang 1 , Yan Zhou 1 , Hong-Bin Huang 2 , Jun Du 1 , Hong-Sheng Wang 1 1 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China 2 Department of Pharmacy, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 3 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China 4 Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China * These author contributed equally to this work Correspondence to: Hong-Sheng Wang, e-mail: whongsh@mail.sysu.edu.cn , hongshengwang@foxmail.com Jun Du, e-mail: dujun@mail.sysu.edu.cn Keywords: ERRα, XCT-790, TNBC, ROS, growth arrest Received: September 25, 2015 Accepted: January 23, 2016 Published: February 09, 2016 ABSTRACT There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and IκBα, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-κB attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-κB/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERRα-based therapies for TNBC patients.