title: Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.
abstract: Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or "arylquins" induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure-activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [(3)H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA. dwatt@uky.edu and Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
authors.forename: Vitaliy M
authors.initials: VM
authors.lastname: Sviripa
authors.affiliation: Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, KY 40506-9983, USA. vmrang01@uky.edu and Lucille Parker Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0096, USA.
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Josiah M
authors.initials: JM
authors.lastname: Obiero
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Yaxia
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA. dwatt@uky.edu and Lucille Parker Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0096, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA. oleg.tsodikov@uky.edu.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
authors.affiliation: Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, KY 40506-9983, USA. vmrang01@uky.edu and Lucille Parker Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0096, USA.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA. dwatt@uky.edu and Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014746:Vimentin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D051638:Ether-A-Go-Go Potassium Channels; C000717247:HSPA5 protein, human; D015363:Quinolones; D014746:Vimentin; C101296:prostate apoptosis response-4 protein