Characterization of a selective inverse agonist for estrogen related receptor α as a potential agent for breast cancer

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• 作者：Liudi Zhang^a ; Peihong Liu^b ; Haifei Chen^c ; Qunyi Li^a ; ^c ; ^{qyli1234@163.com" class="auth_mail" title="E-mail the corresponding author} ; Lu Chen^c ; Huijie Qi^c ; Xiaojin Shi^a ; ^c ; Yongli Du^b ; ^{ylduyjs@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Estrogen related receptor α ; Inverse agonist ; Breast cancer xenograft ; Antitumor agent ; Proliferation ; Migration
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：789
• 期：Complete
• 页码：439-448
• 全文大小：2027 K

文摘

The estrogen-related receptor α (ERRα) is an orphan nuclear receptor that plays a primary role in the regulation of cellular energy homeostasis and osteogenesis. It is reported that ERRα is widely expressed in a range of tissues and accumulating evidence has supported that the high expression of ERRα correlates with poor prognosis of various human malignancies, including breast, endometrium, colon, prostate and ovary cancers. Herein is described the discovery of a novel selective inverse agonist (HSP1604) of ERRα, but not of ERRβ and ERRγ, as determined using transient transfection luciferase reporter assay and a time-resolved fluorescence resonance energy transfer (TR-FRET) co-activator assay. HSP1604 potently inhibits ERRα transcriptional activity with IC₅₀=1.47±0.17 μM in cell-based luciferase reporter assay and also decreases the protein level of ERRα and the mRNA levels of its downstream target genes such as pyruvate dehydrogenase kinase 4 (PDK4), pS2 and osteopontin. HSP1604 has also suppressed the proliferation of different human cancer cell lines and the migration of breast cancer cells with high expression of ERRα. Representative in vivo results show that HSP1604 suppresses the growth of human breast cancer xenograft in nude mice as doses at 30 mg/kg or 100 mg/kg administered every other day during 28-day period. HSP1604 thus has the potential both as a new agent to inhibit the growth of tumors and as a chemical probe of ERRα biology.