The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53

Abstract

The orphan nuclear receptor TR3 (NR41A, Nur77) is overexpressed in most lung cancer patients and is a negative prognostic factor for patient survival. The function of TR3 was investigated in non-small cell lung cancer A549 and H460 cells, and knockdown of TR3 by RNA interference (siTR3) inhibited cancer cell growth and induced apoptosis. The prosurvival activity of TR3 was due, in part, to formation of a p300/TR3/Sp1 complex bound to GC-rich promoter regions of survivin and other Sp-regulated genes (mechanism 1). However, in p53 wild-type A549 and H460 cells, siTR3 inhibited the mTORC1 pathway and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2 which subsequently activated the mTORC1 inhibitor AMPKα (mechanism 2). This demonstrates that the pro-oncogenic activity of TR3 in lung cancer cells was due to inhibition of p53 and activation of mTORC1. 1,1-Bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) is a recently discovered inhibitor of TR3 which mimics the effects of siTR3. DIM-C-pPhOH inhibited growth and induced apoptosis in lung cancer cells and lung tumors in murine orthotopic and metastatic models, and this was accompanied by decreased expression of survivin and inhibition of mTORC1 signaling, demonstrating that inactivators of TR3 represent a novel class of mTORC1 inhibitors.

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

“…UV radiation activates the expression of Sesn1 and Sesn2 through p53 (10,14). p53-responsive elements were identified in the first exon and 9.6 kb downstream of the Sesn2 gene (29,30). These studies suggest that Sesn2 is a tumor suppressor.…”

LKB1/AMPK/mTOR Signaling Pathway in Non-small-cell Lung Cancer

“…In a recent study, another TR3-dependent pro-oncogenic pathway was identified in NSCLC cells. Inactivated TR3 by either siTR3 or DIM-C-pPhOH, an inhibitor of TR3, both inhibited NSCLC cell growth and induced apoptosis (Lee et al, 2012). In p53 wildtype A549 and H460 cells, siTR3 or DIM-C-pPhOH respectively inhibited the mTORC1 pathway, and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2, which subsequently activated the mTORC1 inhibitor AMPKα (mechanism 2) (Lee et al, 2012).…”

“…Inactivated TR3 by either siTR3 or DIM-C-pPhOH, an inhibitor of TR3, both inhibited NSCLC cell growth and induced apoptosis (Lee et al, 2012). In p53 wildtype A549 and H460 cells, siTR3 or DIM-C-pPhOH respectively inhibited the mTORC1 pathway, and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2, which subsequently activated the mTORC1 inhibitor AMPKα (mechanism 2) (Lee et al, 2012). Thus, both siTR3 and DIM-C-pPhOH decreased or deactivated TR3, respectively, to inhibit growth and survival of NSCLC cells by inhibition of the mTORC1 pathway via p53/sestrin-dependent activation of AMPKα.…”

Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-InflammatoryPara-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson’s Disease

“…The mechanism underlying this anti-inflammatory activity in glia involved stabilization of nuclear corepressor proteins that prevented DNA binding of NF-kB at cis elements in the Nos2 promoter. Because C-DIM5 and C-DIM12 are activators in cancer cell lines of the NR4A family nuclear receptors Nur77 and Nurr1, respectively (Inamoto et al, 2008;Lee et al, 2010Lee et al, , 2012Li et al, 2012), they may exert neuroprotective effects by broadly suppressing NF-kB-dependent expression of inflammatory genes in glia, as suggested in recent studies characterizing the neuroprotective role of Nurr1 in PD, and warrants further study (Saijo et al, 2009). Examination of the three C-DIM compounds used in the present studies indicate that, although these compounds may have similar neuroprotective activities in vitro, the differing substituents on the aryl ring yield distinct pharmacokinetic profiles, which may in part be responsible for the differences in efficacy observed in vivo.…”