Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.

Vitaliy M Sviripa, Ravshan Burikhanov, Josiah M Obiero, Yaxia Yuan, Justin R Nickell, Linda P Dwoskin, Chang-Guo Zhan, Chunming Liu, Oleg V Tsodikov, Vivek M Rangnekar, David S Watt

Organic & biomolecular chemistry 2016 Jan 7

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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.

Citation

Vitaliy M Sviripa, Ravshan Burikhanov, Josiah M Obiero, Yaxia Yuan, Justin R Nickell, Linda P Dwoskin, Chang-Guo Zhan, Chunming Liu, Oleg V Tsodikov, Vivek M Rangnekar, David S Watt. Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin. Organic & biomolecular chemistry. 2016 Jan 7;14(1):74-84