Abstract
The tumor suppressor protein prostate apoptosis response-4 (Par-4), which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently induces paracrine apoptosis of tumor cells.
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Acknowledgements
This work was supported by National Center for Research Resources through 'COBRE Center for Biomedical Research Excellence' grant P20 RR020171 (to L. Hersh, who is the principal investigator of the study on which D.S.W. is core director), NIH–National Cancer Institute grants R01 CA60872 and R21 CA179283 (to V.M.R.) and University of Kentucky Center for Clinical and Translational Science Drug Discovery Pilot grant (to V.M.R., D.S.W. and C.L.).
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R.B. contributed to experimental biological studies; V.M.S. contributed to arylquin organic syntheses; N.H. contributed to experimental biological studies; W.Z. contributed to experimental biological studies; W.J.L. contributed to NMR studies characterizing arylquins; A.H. contributed to computational studies; C.-G.Z. contributed to computational studies; D.S.W. contributed to the design of arylquin syntheses; C.L. contributed to biological studies of biotinylated arylquin; and V.M.R. contributed to the design of Par-4 biological studies.
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V.M.R., D.S.W. and C.L. hold 30% equity each in a limited liability corporation, Curonc LLC, founded for the purpose of advancing translational research involving arylquins, and the University of Kentucky has filed a preliminary patent application for these compounds in which these authors are co-inventors.
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Burikhanov, R., Sviripa, V., Hebbar, N. et al. Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat Chem Biol 10, 924–926 (2014). https://doi.org/10.1038/nchembio.1631
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DOI: https://doi.org/10.1038/nchembio.1631
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