Open AccessDevelopment of hybrid small molecules that induce degradation of estrogen receptor‐alpha and necrotic cell death in breast cancer cells
Author(s) -
Okuhira Keiichiro,
Demizu Yosuke,
Hattori Takayuki,
Ohoka Nobumichi,
Shibata Norihito,
NishimakiMogami Tomoko,
Okuda Haruhiro,
Kurihara Masaaki,
Naito Mikihiko
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12272
Subject(s) - estrogen receptor , programmed cell death , proteasome , cancer research , proteasome inhibitor , estrogen receptor alpha , microbiology and biotechnology , ubiquitin , protein degradation , downregulation and upregulation , apoptosis , biology , chemistry , cancer , medicine , breast cancer , biochemistry , gene
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 ( S pecific and N on‐genetic I AP ‐dependent P rotein ER aser) that induces degradation of target proteins via ubiquitin‐proteasome system. Here we report the activities of SNIPER ( ER ) that targets estrogen receptor alpha ( ER α) for degradation. SNIPER ( ER ) induced degradation of ER α and inhibited estrogen‐dependent expression of pS 2 gene in an estrogen‐dependent breast cancer cell line MCF ‐7. A proteasome inhibitor MG 132 and si RNA ‐mediated downregulation of cIAP 1 abrogated the SNIPER ( ER )‐induced ER α degradation, suggesting that the ER α is degraded by proteasome subsequent to cIAP 1‐mediated ubiquitylation. Intriguingly, after the ER α 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 HMGB 1, a marker of necrosis, from the cells. Following the ER α 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 ER α degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER ( ER ) as a lead for the treatment of ER α‐positive breast cancers.