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Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis.

Burikhanov R, Sviripa VM, Hebbar N, Zhang W, Layton WJ, Hamza A, Zhan CG, Watt DS, Liu C, Rangnekar VM - Nat. Chem. Biol. (2014)

Bottom Line: The tumor suppressor protein prostate apoptosis response-4 (Par-4), which is secreted by normal cells, selectively induces apoptosis in cancer cells.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky, USA. [2].

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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Arylquin 1 displaces Par-4 bound to vimentin to induce Par-4 secretiona. Chemical structure of Arylquin 1. Arylquin 1 contains 2-amino and 7-(N,N-dimethyl)amino substituents on the quinoline ring and an ortho-fluorine on the C-3 aryl group.b. Arylquin 1 induces dose-dependent secretion of Par-4. MEF cells were treated with the indicated concentrations of Arylquin 1 or vehicle (V), and Par-4 in the conditioned medium (CM) or whole-cell lysate was quantified by Western blot analysis. Albumin or collagen 1A1 in the CM, or intracellular β-actin in the lysate served as a loading control. Uncut gels for Figure 1b can be found in Supplementary Figure 17.c. Par-4 co-localizes with vimentin and is displaced from vimentin by Arylquin 1 treatment of cells. HEL cells, treated with vehicle or Arylquin 1 (500 nM) for 24 h, were subjected to ICC for Par-4 (red fluorescence) and vimentin (green fluorescence). Cells were stained with DAPI to reveal their nuclei (cyan fluorescence). Colocalization of Par-4 and vimentin in the Overlay images shown in vehicle panel is indicated by arrowheads (yellow fluorescence), and dissociation of Par-4 and vimentin (loss of yellow fluorescence, but retention of red and green fluorescence) is indicated by arrows in the Arylquin 1 panel.
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Figure 1: Arylquin 1 displaces Par-4 bound to vimentin to induce Par-4 secretiona. Chemical structure of Arylquin 1. Arylquin 1 contains 2-amino and 7-(N,N-dimethyl)amino substituents on the quinoline ring and an ortho-fluorine on the C-3 aryl group.b. Arylquin 1 induces dose-dependent secretion of Par-4. MEF cells were treated with the indicated concentrations of Arylquin 1 or vehicle (V), and Par-4 in the conditioned medium (CM) or whole-cell lysate was quantified by Western blot analysis. Albumin or collagen 1A1 in the CM, or intracellular β-actin in the lysate served as a loading control. Uncut gels for Figure 1b can be found in Supplementary Figure 17.c. Par-4 co-localizes with vimentin and is displaced from vimentin by Arylquin 1 treatment of cells. HEL cells, treated with vehicle or Arylquin 1 (500 nM) for 24 h, were subjected to ICC for Par-4 (red fluorescence) and vimentin (green fluorescence). Cells were stained with DAPI to reveal their nuclei (cyan fluorescence). Colocalization of Par-4 and vimentin in the Overlay images shown in vehicle panel is indicated by arrowheads (yellow fluorescence), and dissociation of Par-4 and vimentin (loss of yellow fluorescence, but retention of red and green fluorescence) is indicated by arrows in the Arylquin 1 panel.

Mentions: Within this library of compounds, the fluorinated 3-arylquinolines proved particularly promising in promoting Par-4 secretion. Structure-activity studies defined that 3-arylquinolines, such as Arylquin 1 (1) (Figure 1a and Supplementary Figure 2), was most active as the leading member of a new class of “small-molecule” Par-4 secretagogues. Arylquin 1 produced a dose-dependent secretion in MEF cells (Figure 1b). Arylquin 1 also induced robust secretion of Par-4 in normal/immortalized human cells, but failed to induce the secretion of Par-4 in a panel of lung tumor cells (Supplementary Figure 3). By contrast, prostate cancer cells showed induction of Par-4 secretion with Arylquin 1 relative to vehicle control (Supplementary Figure 3). Consistent with previous studies 5, Brefeldin A, which blocked anterograde endoplasmic reticulum-Golgi traffic, inhibited basal as well as Arylquin 1-inducible Par-4 secretion (Supplementary Figure 3). These findings indicated that Arylquin 1 regulated Par-4 secretion via the classical secretory pathway.


Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis.

Burikhanov R, Sviripa VM, Hebbar N, Zhang W, Layton WJ, Hamza A, Zhan CG, Watt DS, Liu C, Rangnekar VM - Nat. Chem. Biol. (2014)

Arylquin 1 displaces Par-4 bound to vimentin to induce Par-4 secretiona. Chemical structure of Arylquin 1. Arylquin 1 contains 2-amino and 7-(N,N-dimethyl)amino substituents on the quinoline ring and an ortho-fluorine on the C-3 aryl group.b. Arylquin 1 induces dose-dependent secretion of Par-4. MEF cells were treated with the indicated concentrations of Arylquin 1 or vehicle (V), and Par-4 in the conditioned medium (CM) or whole-cell lysate was quantified by Western blot analysis. Albumin or collagen 1A1 in the CM, or intracellular β-actin in the lysate served as a loading control. Uncut gels for Figure 1b can be found in Supplementary Figure 17.c. Par-4 co-localizes with vimentin and is displaced from vimentin by Arylquin 1 treatment of cells. HEL cells, treated with vehicle or Arylquin 1 (500 nM) for 24 h, were subjected to ICC for Par-4 (red fluorescence) and vimentin (green fluorescence). Cells were stained with DAPI to reveal their nuclei (cyan fluorescence). Colocalization of Par-4 and vimentin in the Overlay images shown in vehicle panel is indicated by arrowheads (yellow fluorescence), and dissociation of Par-4 and vimentin (loss of yellow fluorescence, but retention of red and green fluorescence) is indicated by arrows in the Arylquin 1 panel.
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Figure 1: Arylquin 1 displaces Par-4 bound to vimentin to induce Par-4 secretiona. Chemical structure of Arylquin 1. Arylquin 1 contains 2-amino and 7-(N,N-dimethyl)amino substituents on the quinoline ring and an ortho-fluorine on the C-3 aryl group.b. Arylquin 1 induces dose-dependent secretion of Par-4. MEF cells were treated with the indicated concentrations of Arylquin 1 or vehicle (V), and Par-4 in the conditioned medium (CM) or whole-cell lysate was quantified by Western blot analysis. Albumin or collagen 1A1 in the CM, or intracellular β-actin in the lysate served as a loading control. Uncut gels for Figure 1b can be found in Supplementary Figure 17.c. Par-4 co-localizes with vimentin and is displaced from vimentin by Arylquin 1 treatment of cells. HEL cells, treated with vehicle or Arylquin 1 (500 nM) for 24 h, were subjected to ICC for Par-4 (red fluorescence) and vimentin (green fluorescence). Cells were stained with DAPI to reveal their nuclei (cyan fluorescence). Colocalization of Par-4 and vimentin in the Overlay images shown in vehicle panel is indicated by arrowheads (yellow fluorescence), and dissociation of Par-4 and vimentin (loss of yellow fluorescence, but retention of red and green fluorescence) is indicated by arrows in the Arylquin 1 panel.
Mentions: Within this library of compounds, the fluorinated 3-arylquinolines proved particularly promising in promoting Par-4 secretion. Structure-activity studies defined that 3-arylquinolines, such as Arylquin 1 (1) (Figure 1a and Supplementary Figure 2), was most active as the leading member of a new class of “small-molecule” Par-4 secretagogues. Arylquin 1 produced a dose-dependent secretion in MEF cells (Figure 1b). Arylquin 1 also induced robust secretion of Par-4 in normal/immortalized human cells, but failed to induce the secretion of Par-4 in a panel of lung tumor cells (Supplementary Figure 3). By contrast, prostate cancer cells showed induction of Par-4 secretion with Arylquin 1 relative to vehicle control (Supplementary Figure 3). Consistent with previous studies 5, Brefeldin A, which blocked anterograde endoplasmic reticulum-Golgi traffic, inhibited basal as well as Arylquin 1-inducible Par-4 secretion (Supplementary Figure 3). These findings indicated that Arylquin 1 regulated Par-4 secretion via the classical secretory pathway.

Bottom Line: The tumor suppressor protein prostate apoptosis response-4 (Par-4), which is secreted by normal cells, selectively induces apoptosis in cancer cells.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky, USA. [2].

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.

Show MeSH
Related in: MedlinePlus