Abstract
The orphan nuclear receptor TR3 (NR41A and 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/ specificity protein 1 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 AMP-activated protein kinase α (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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Aged
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Animals
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Carcinoma, Non-Small-Cell Lung / diagnosis
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Female
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Gene Expression Regulation, Neoplastic* / drug effects
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Gene Knockdown Techniques
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Humans
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Indoles / pharmacology
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Lung Neoplasms / diagnosis
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology*
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Middle Aged
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Multiprotein Complexes
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Nuclear Proteins / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 1 / deficiency
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
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Phenols / pharmacology
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Prognosis
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Proteins / metabolism*
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RNA Interference
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Signal Transduction* / drug effects
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TOR Serine-Threonine Kinases
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Tumor Suppressor Protein p53 / genetics*
Substances
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1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane
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Indoles
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Multiprotein Complexes
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Nuclear Proteins
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Phenols
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Proteins
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SESN2 protein, human
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Tumor Suppressor Protein p53
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases