title: 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.
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.
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Zhuo-Jia
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
authors.forename: Guan-Min
authors.initials: GM
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Kun-Shui
authors.initials: KS
authors.lastname: Zhang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Liang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Huang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009570:Nitriles / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013844:Thiazoles; D000097983:ERRalpha Estrogen-Related Receptor; C488234:XCT790
keywords: ERRα; ROS; TNBC; XCT-790; growth arrest