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.

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<div>Abstract<p>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-pPhCF₃⁺MeSO₃⁻ (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 Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.</p></div>

<p>The Supplementary Methods show the Synthesis of DIM-C-pPhCF3+MeSO3- (BI1071); Figure S1 shows BI1071 induces apoptosis in different cancer cell lines; Fig. S2 shows BI1071 induces apoptosis in different breast cancer cell lines; Fig. S3 shows BI1071 induces apoptosis in cancer cell lines but not in non-transformed cell lines; Fig. S4 shows BI1071 did't induce the body weight loss; Fi.g S5 shows overexpression of Nur77-LBD enhances the killing effect of BI1071; Fig. S6 shows BI1071 has no effect on other nuclear receptors; Fig. S7 shows the imparied effect of BI1071 could be rescued by re-expression of Bcl-2; Fig. S8 shows BI1071 binding to Nur77 promotes Nur77 interaction with Bcl-2 and mitochondrial localization</p>

<p>The Supplementary Methods show the Synthesis of DIM-C-pPhCF3+MeSO3- (BI1071); Figure S1 shows BI1071 induces apoptosis in different cancer cell lines; Fig. S2 shows BI1071 induces apoptosis in different breast cancer cell lines; Fig. S3 shows BI1071 induces apoptosis in cancer cell lines but not in non-transformed cell lines; Fig. S4 shows BI1071 did't induce the body weight loss; Fi.g S5 shows overexpression of Nur77-LBD enhances the killing effect of BI1071; Fig. S6 shows BI1071 has no effect on other nuclear receptors; Fig. S7 shows the imparied effect of BI1071 could be rescued by re-expression of Bcl-2; Fig. S8 shows BI1071 binding to Nur77 promotes Nur77 interaction with Bcl-2 and mitochondrial localization</p>