Par 4 secretion: stoichiometry of 3 arylquinoline binding to vimentin.
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.
Organic biomolecular chemistry