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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 [3H]-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.

Original languageEnglish
Pages (from-to)74-84
Number of pages11
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number1
DOIs
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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