title: Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer.
abstract: Clusterin is a stress-activated, cytoprotective chaperone that confers broad-spectrum treatment resistance in cancer. However, the molecular mechanisms mediating CLU transcription following anticancer treatment stress remain incompletely defined. We report that Y-box binding protein-1 (YB-1) directly binds to CLU promoter regions to transcriptionally regulate clusterin expression. In response to endoplasmic reticulum stress inducers, including paclitaxel, YB-1 is translocated to the nucleus to transactivate clusterin. Furthermore, higher levels of activated YB-1 and clusterin are seen in taxane-resistant, compared with parental, prostate cancer cells. Knockdown of either YB-1 or clusterin sensitized prostate cancer cells to paclitaxel, whereas their overexpression increased resistance to taxane. Clusterin overexpression rescued cells from increased paclitaxel-induced apoptosis following YB-1 knockdown; in contrast, however, YB-1 overexpression did not rescue cells from increased paclitaxel-induced apoptosis following clusterin knockdown. Collectively, these data indicate that YB-1 transactivation of clusterin in response to stress is a critical mediator of paclitaxel resistance in prostate cancer.
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors: Masaki
authors: M
authors: Shiota
authors: Amina
authors: A
authors: Zoubeidi
authors: Masafumi
authors: M
authors: Kumano
authors: Eliana
authors: E
authors: Beraldi
authors: Seiji
authors: S
authors: Naito
authors: Colleen C
authors: CC
authors: Nelson
authors: Poul H B
authors: PH
authors: Sorensen
authors: Martin E
authors: ME
authors: Gleave
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering; D043823:Taxoids / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D001952:Bridged-Ring Compounds; D051152:Clusterin; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D034741:RNA, Small Interfering; D043823:Taxoids; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C080625:taxane; C112765:tanespimycin; D017239:Paclitaxel; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde