title: Nelfinavir and nelfinavir analogs block site-2 protease cleavage to inhibit castration-resistant prostate cancer.
abstract: Nelfinavir and its analogs inhibit proliferation and induce apoptosis of castration-resistant prostate cancer through inhibition of site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. Western blotting in nelfinavir and its analog treated cells confirms accumulation of precursor SREBP-1 and ATF6. Nelfinavir and its analogs inhibit human homolog M. jannaschii S2P cleavage of an artificial protein substrate CED-9 in an in vitro proteolysis assay in a dose-dependent manner. Nelfinavir and its analogs are more potent inhibitors of S2P cleavage activity than 1,10-phenanthroline, a metalloprotease-specific inhibitor. Further, cluster analysis of gene expression from treated DU145 and PC3 cell lines demonstrate a close similarity of nelfinavir, its analogs, and 1,10-phenanthroline. These results show nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of S2P cleavage activity. This leads to accumulation of precursor SREBP-1 and ATF6, and development of insufficient reserves of their transcriptionally-active forms. The present results validate S2P and regulated intramembrane proteolysis as novel therapeutic targets for castration-resistant prostate cancer therapeutics. A clinical trial of nelfinavir or its analogs should be developed for castration-resistant prostate cancer.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Guan
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA [2] Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Chow
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063746:Methanocaldococcaceae / Q000201:enzymology; D019888:Nelfinavir / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012313:RNA / Q000032:analysis; D017423:Sequence Analysis, RNA; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D059467:Transcriptome
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D011498:Protein Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D012313:RNA; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human; D019888:Nelfinavir