학술논문
Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models
Document Type
Academic Journal
Author
Nappi, Lucia; Aguda, Adeleke H.; Nakouzi, Nader Al; Lelj-Garolla, Barbara; Beraldi, Eliana; Lallous, Nada; Thi, Marisa; Moore, Susan; Fazli, Ladan; Battsogt, Dulguun; Stief, Sophie; Ban, Fuqiang; Nguyen, Nham T.; Saxena, Neetu; Dueva, Evgenia; Zhang, Fan; Yamazaki, Takeshi; Zoubeidi, Amina; Cherkasov, Artem; Brayer, Gary D.; Gleave, Martin
Source
Journal of Clinical Investigation. February, 2020, Vol. 130 Issue 2, p699, 16 p.
Subject
Language
English
ISSN
0021-9738
Abstract
HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti-androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.
Introduction Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones characterized by a conserved [alpha]-crystallin domain located between a highly flexible, variable C-terminal region and a poorly conserved, disorganized N-terminal [...]
Introduction Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones characterized by a conserved [alpha]-crystallin domain located between a highly flexible, variable C-terminal region and a poorly conserved, disorganized N-terminal [...]