Abstract 4009: Regulation of mTOR pathway by the orphan nuclear receptor NR4A1 (TR3/Nur77) in non-small cell lung cancer: Role of TR3 in AMPK activation

Abstract

Abstract The orphan nuclear receptor NR4A1 (TR3/Nur77) is overexpressed as a nuclear protein in multiple human tumors and this receptor exhibits pro-oncogenic activity in many tumor types. A recent study in this laboratory has shown that deactivation of TR3 decreases proliferation and induces apoptosis through inhibition of Sp1-dependent anti-apoptotic genes. In this study, we show that TR3 is overexpressed in human non-small cell lung cancer (NSCLC) tissues compared with adjacent normal lung tissues and high TR3 expression levels are correlated with shorter survival for patients with NSCLC (P = 0.0112). Treatment of NSCLC cells with small interfering RNAs for TR3 or the TR3 deactivator, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), decreased cell proliferation and induced apoptosis through dual-targeting of mTOR pathway and Sp1 transcription factor. Knockdown of TR3 inhibited mTOR and its two major downstream targets, p70S6K and 4E-BP1 through LKB1-independent activation of AMPK but not through inactivation of AKT nor Sp1. We also observed that AMPK activation by TR3 knockdown is primarily due to induction of sestrin2 by enhancing p53-dependent transactivation activity. Furthermore, DIM-C-pPhOH (30 mg/kg/day) induced apoptosis and inhibited tumor growth in an orthotopic mouse model of human NSCLC, and decreased tumor number and size in a lung metastatic tumor model using tail vein injection. These results demonstrate for the first time that endogenous nuclear TR3 regulates AMPK-mediated mTOR pathway and TR3 deactivation represents a novel approach for treatment of NSCLC. Grant support: National Institutes of Health (R01CA124998) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4009. doi:10.1158/1538-7445.AM2011-4009