title: Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells.
abstract: Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces degradation of target proteins via ubiquitin-proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ERα) for degradation. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer cell line MCF-7. A proteasome inhibitor MG132 and siRNA-mediated downregulation of cIAP1 abrogated the SNIPER(ER)-induced ERα degradation, suggesting that the ERα is degraded by proteasome subsequent to cIAP1-mediated ubiquitylation. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ERα degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)-treated MCF-7 cells, and an anti-oxidant N-acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers.
authors.affiliation: Division of Biochemistry and Molecular Biology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Okuhira
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Demizu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009336:Necrosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017382:Reactive Oxygen Species; D046988:Proteasome Endopeptidase Complex