title: Radicicol induces intracellular accumulation of glycan-deficient clusterin variant.
abstract: Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the mechanistic basis, this variant proved to be a product disposed from the stressed ER. During this process, inhibitory effect of radicicol on protein degradation results in cytosolic accumulation of glycan-deficient clusterin variant that signals cell death. These results provide a therapeutic insight into the targeted proteostasis perturbation of clusterin as an anti-cancer strategy.
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors: Ilho
authors: I
authors: Choi
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors: Yumi
authors: Y
authors: Lee
authors: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors: Joong-Yeol
authors: JY
authors: Park
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors: Youngsup
authors: Y
authors: Song
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors: Eun-Ju
authors: EJ
authors: Chang
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea. Electronic address: swkang@amc.seoul.kr.
authors: Sang-Wook
authors: SW
authors: Kang
mesh_terms: D045744:Cell Line, Tumor; D051152:Clusterin / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects
chemical_list: D051152:Clusterin; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; C035359:monorden
keywords: Clusterin; ER stress; Proteostasis; Radicicol