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Nuclear Receptor 4A1 As a Drug Target for Breast Cancer Chemotherapy

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Nuclear Receptor 4A1 As a Drug Target for Breast Cancer Chemotherapy E Hedrick et al. NR4A1, indole derivative, 22:5 831–840 Research antagonists Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy Erik Hedrick, Syng-Ook Lee1, Ravi Doddapaneni2, Mandip Singh2 and Stephen Safe Correspondence Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, should be addressed Texas 77843-4466, USA to S Safe or M Singh 1Department of Food Science and Technology, Keimyung University, Daegu 704701, Republic of Korea Emails 2Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, [email protected] or Tallahassee, Florida 32307, USA [email protected] Abstract The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and Key Words breast cancer cell lines. The functional activity of this receptor was investigated by RNA " NR4A1 interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with " indole derivative NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected " antagonists with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA- MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced Endocrine-Related Cancer apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(30-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor. Endocrine-Related Cancer (2015) 22, 831–840 Introduction Nuclear receptor 4A1 (NR4A1, Nur77, TR3) is a member Pearen & Muscat 2010, Lee et al.2011). NR4A1 is over- of the NR4A orphan receptor sub-family of nuclear receptors. expressed in multiple tumors and cancer cell lines. Results of NR4A receptors (NR4A1, NR4A2, and NR4A3) play essential receptor knockdown by RNA interference (RNAi) demon- roles in metabolic processes, inflammation, vascular func- strate that in solid tumors the receptor is pro-oncogenic and tion, steroidogenesis, and the CNS (Maxwell & Muscat 2006, regulates cell growth and survival (Uemura & Chang 1998, http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0063 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 07:23:55AM via free access Research E Hedrick et al. NR4A1, indole derivative, 22:5 832 antagonists A Bras et al.2000, Kolluri et al. 2003, Zeng et al.2006, Lee et al. TR3 1 siNR4A1 3 p300 2010, 2011, 2012, 2014a, Wu et al.2011). Several pro- or C-DIM Sp1 p53 GC H apoptotic agents including phorbol esters and adamantyl- + 2 C R Stress derived retinoids induce expression and nuclear export of Sestrin Anti-apoptotic TXNDC5/IDH1 genes (survivin, N NR4A1 which subsequently binds mitochondrial bcl-2 to 2 bcl2, etc.) H form a pro-apoptotic complex that decreases mitochondrial C-DIM mTOR complex membrane potential (Li et al.2000, Lin et al. 2004, Zhang Inhibition Inhibition of cell of mTOR growth/survival 2007). This has led to the development of peptide mimics B MCF-7 MDA-MB-231 SKBR3 120 that convert bcl-2 into an apoptotic complex; similar results 120 120 100 100 100 80 * 80 have been reported for the taxane-derived anticancer agent * 80 * * 60 * 60 60 * et al et al 40 40 40 paclitaxel (Kolluri . 2008, Ferlini . 2009). 20 20 20 Cell number (%) Cell number 0 0 0 Cytosporone B and related analogs have been identified as siCtl + –– ++–– –– siNR4A1 – ++– + +– ++ ligands for NR4A1 (Zhan et al.2008, Liu et al. 2010), and two C MCF-7 (24 h) MDA-MB-231 (24 h) SKBR3 (24 h) additional compounds, (ethyl 2-(2,3,4-trimethoxy-6-(1-oct- 120 120 120 100 100 * 100 * * anoyl)phenyl)acetate and 1-(3,4,5-trihydroxyphenyl) 80 80 * 80 * * 60 60 60 * * * no-nan-1-one), also bind NR4A1 (Zhan et al.2012, Wang 40 40 40 20 20 20 Cell number (%) Cell number 0 0 0 et al. 2014). Ethyl 2-(2,3,4-trimethoxy-6-(1-oct-anoyl) μ DIM-C-pPhCO2Me ( M) 0 7.5 15 20 07.51520 0 7.5 15 20 phenyl)acetate inactivates nuclear NR4A1, whereas D 3.00 1400 1-(3,4,5-trihydroxyphenyl)no-nan-1-one and cytosporone 2.50 1200 1000 2.00 * ) * 3 800 B induce nuclear export of NR4A1. 1.50 * 600 * 1.00 (mm 400 Studies in this laboratory have been investigating 0.50 Tumor volumes Tumor 200 0 (g) weights Tumor 0.00 0 aseriesof1,1-bis(3 -indolyl)-1-(p-substituted phenyl) Control + – – Control + – – DIM-C-pPhCO2Me – + – DIM-C-pPhCO2Me – + – methane (C-DIM) analogs and their effects on NR4A1 and DIM-C-pPhCN – – + DIM-C-pPhCN – – + et al E MCF-7 MDA-MB-231 SKBR3 NR4A1-dependent transactivation (Chintharlapalli . 120 120 120 100 100 ** 100 ** 2005, Lee et al. 2009, 2010, 2012, 2014a,b, Cho et al. 2010). 80 * 80 80 60 60 60 * * * Since NR4A1 exhibits pro-oncogenic activity, we have been 40 40 40 20 20 20 focused on the identification of C-DIMs that inactivate (%) Cell number 0 0 0 siCtl ++–– ++––++ –– NR4A1. The p-hydroxyphenyl analog (DIM-C-pPhOH) was siNR4A1 – – ++– – ++– – ++ Endocrine-Related Cancer DMSO DIM-C-pPhCO Me characterized as a compound that inactivated nuclear 2 NR4A1 in cancer cell lines but this was not accompanied by nuclear export of NR4A1 (Lee et al. 2010, 2012, 2014a). Figure 1 NR4A1-regulated pathways and effects of NR4A1 knockdown on breast Subsequent studies comparing the effects of DIM-C-pPhOH cancer cell proliferation. (A) NR4A1-regulated pathways/genes that can be and knockdown of NR4A1 (siNR4A1) by RNAi identified targeted by C-DIM/NR4A1 antagonists. (B) Cells were transfected with two three major pro-oncogenic pathways and associated genes siNR4A1 oligonucleotides (1 and 2) and cell numbers were determined after 72 h. (C) Cells were treated with different concentrations of regulated by NR4A1 that were inhibited by DIM-C-pPhOH: DIM-C-pPhCO2Me for 24 h and the number of cells were then determined. i) NR4A1 regulates expression of genes such as survivin (D) Athymic nude mice bearing MDA-MB-231 cells (orthotopic) were through interactions with specificity protein 1 (Sp1) bound administered corn oil (control), DIM-C-pPhCO2Me or DIM-C-pPhCN (50 mg/kg per day) by oral gavage for 28 days, and effects on tumor growth to their proximal GC-rich promoters (Lee et al. 2010); and weight were determined (significantly decreased; *P!0.01). (E) Cells ii) NR4A1 inactivates p53 to enhance mTOR signaling in were transfected with siCtl (non-specific oligonucleotide) or siNR4A1 and lung and colon cancer cells expressing WT p53 (Lee et al. then treated with 20 mM DIM-C-pPhCO2Me for 24 h and the number of cells were then counted. The control (untreated) groups (set at 100%) in studies 2012, 2014b); and iii) NR4A1 regulates expression of on the growth inhibitory effects of C-DIMs after knockdown are cells thioredoxin domain-containing 5 (TXNDC5) and isoci- transfected with siNR4A1 and treated with DMSO. Results (B, C and D) are G trate dehydrogenase 1 (IDH1) to maintain low levels of means S.E.M. for at least three separate determinations for each treatment group. Significant (P!0.05) growth inhibition is indicated (*) and a et al a oxidative stress (Lee . 2014 ; Fig. 1A). significant decrease in the growth inhibitory effects of DIM-C-pPhCO2Me Recent studies show that NR4A1 is overexpressed in after NR4A1 knockdown is also indicated (**). ER-positive and ER-negative breast tumors (Muscat et al. 2013). NR4A1 expression in breast tumors is correlated et al. 2010). However, a recent study reported pro-migratory with decreased relapse-free survival (Zhou et al. 2014). activity for this receptor (Zhou et al. 2014). Research in this Results of NR4A1 overexpression in breast cancer cells laboratory has demonstrated pro-oncogenic functions of suggest that NR4A1 may be anti-migratory (Alexopoulou NR4A1 in pancreatic, colon, and lung cancer cells. This http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0063 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 07:23:55AM via free access Research E Hedrick et al. NR4A1, indole derivative, 22:5 833 antagonists study investigates the functions of this receptor in breast iGL2 (control siRNA) in lipofectamine for 72 h. Cells were cancer cells and the effects of C-DIM/NR4A1 antagonists. then trypsinized and counted using a Coulter Z1 cell counter The results clearly demonstrate the pro-oncogenic and growth inhibition was determined. Each experiment functions of NR4A1 in breast cancer and also demonstrate was carried out in triplicate and results were expressed as the that C-DIM/NR4A1 antagonists represent a potential novel meanGS.E.M. for each set of experiments. Cells were also approach for treating breast cancer patients that over- treated with C-DIMs after NR4A1 knockdown.
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