Oxidized analogs of Di(1H-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity.

Marisa Sanchez,David J Castro,Xihua Cao,Donna Hansel,Robert G Oshima,Michael Cuddy,Vivian Ruvolo,Marcia I Dawson,Zebin Xia,Shu-Ichi Matsuzawa,Dieter A Wolf,Ricardo G Correa,Liqun Chen,Michael Andreeff,Andrey Bobkov,Elizabeth Rico-Bautista,Jinghua Yu,John C Reed,Xiao-Kun Zhang

doi:10.18632/oncotarget.25285

Marisa Sanchez, David J Castro + Show 17 more

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https://doi.org/10.18632/oncotarget.25285

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Di(1H-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF3) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF3, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X+ OMs–s) having CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs– with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3+ OMs– showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF3+ OMs– activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF3+ OMs–, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF3+ OMs– in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.

Highlights

Orphan nuclear receptor 4A1 (NR4A1; human TR3, mouse Nur77) plays roles in regulating cancer cell viability
CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F nuclear magnetic resonance (NMR) spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs– with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1
The data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through unfolded protein response (UPR) signaling downstream of NR4A1 binding

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Introduction

Orphan nuclear receptor 4A1 (NR4A1; human TR3, mouse Nur77) plays roles in regulating cancer cell viability. NR4A1 stimulates cell-cycle progression and proliferation [2,3,4,5] or cell-cycle arrest and death [5,6,7,8,9]. In the cytoplasm NR4A1 signaling is nongenomic and pro-apoptotic through interaction with other proteins [7, 9]. Apoptotic agents can induce nongenomic activity involving NR4A1 over-expression, nuclear export into the cytoplasm and interaction with mitochondrial membranebound Bcl-2 leading to Bcl-2 conformational change and apoptosis [6, 7, 9]. NR4A1 translocates to the endoplasmic reticulum (ER) during ER stress-induced apoptosis [10, 11] leading to loss of ER Ca(II) homeostasis [12]. It was proposed that NR4A1-dependent apoptosis is mediated through two parallel pathways: mitochondria targeting and ER targeting [11]

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