BI1071, a Novel Nur77 Modulator, Induces Apoptosis of Cancer Cells by Activating the Nur77-Bcl-2 Apoptotic Pathway

Abstract

Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF 3 þ MeSO 3 À (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77-and Bcl-2-dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

Reposition of the anti-inflammatory drug diacerein in an in-vivo colorectal cancer model

“…Conversely, Nur77 abolishes the anti-apoptotic effect induced by Bcl-2. After mitochondrial translocation, Nur77 interacts with Bcl-2 and reverses its effect ( Moll et al, 2006 , Zhang, X.k., 2007 ), thus increasing chemosensitivity ( Chen et al, 2019 ). Similarly, our results show that combination treatment upregulated Nur77 gene expression over that mediated by 5-FU monotherapy, a finding that supports the beneficial effect of add-on therapy with Diac.…”

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

“…Apoptosis assay was conducted at 0, 4 and 8 h, using a dead cell apoptosis kit with Annexin V-FITC and propidium iodide (PI) (Thermo, Cat. #V13241) according to the manufacturer’s instructions ( Chen et al, 2019 ; Li et al, 2022 ). MV3 cells were washed with PBS, resuspended in binding buffer, incubated with Annexin V-FITC and PI for 15 min according to the kit protocol, and analyzed immediately by cytoFLEX Flow Cytometry System (Beckman-Coulter) using FITC and PerCP.…”

“…Body weight and tumor volume were measured every 3 days. Mice were sacrificed by CO 2 inhalation after 15-day drug treatment and the tumors were stripped for various assessments ( Chen et al, 2019 ). Nur77 knockout (KO) MV3 cells were generated by CRISPR/Cas9 system using a previously reported method ( Chen et al, 2019 ).…”

“…Mice were sacrificed by CO 2 inhalation after 15-day drug treatment and the tumors were stripped for various assessments ( Chen et al, 2019 ). Nur77 knockout (KO) MV3 cells were generated by CRISPR/Cas9 system using a previously reported method ( Chen et al, 2019 ). The gRNA targeting sequence of Nur77 is 5′-ACC​TTC​ATG​GAC​GGC​TAC​AC-3′.…”

“…Thus, it is possible that venlafaxine can reduce melanoma cell proliferation. In addition, venlafaxine contains a two-ring group, which is commonly seen in many potent Nur77 modulators, i.g., BI1071 and Triclosan ( Ha et al, 2018 ; Chen et al, 2019 ). Venlafaxine is likely to act as a Nur77 modulator, exhibiting anti-cancer activities by regulation of Nur77 signaling.…”