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

S-O Lee1, T Andey, U-H Jin

  • 1Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77843-4466, USA.

Oncogene
|November 15, 2011
PubMed

Insights

The orphan nuclear receptor TR3 promotes lung cancer by inhibiting p53 and activating mTORC1. Inhibiting TR3 with DIM-C-pPhOH halts cancer growth and induces apoptosis, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The orphan nuclear receptor TR3 (NR4A1/Nur77) is overexpressed in lung cancer, correlating with poor patient survival.
  • TR3 plays a pro-oncogenic role in non-small-cell lung cancer (NSCLC).

Purpose of the Study:

  • To elucidate the mechanisms by which TR3 promotes lung cancer growth and survival.
  • To evaluate the therapeutic potential of TR3 inhibition in lung cancer models.

Main Methods:

  • RNA interference (siTR3) to knockdown TR3 expression in NSCLC cell lines (A549, H460).
  • Investigated TR3's role in regulating survivin, Sp-regulated genes, p53, sestrin 2, and the mTORC1 pathway.
  • Utilized 1,1-Bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), a TR3 inhibitor, in cell lines and murine orthotopic/metastatic lung cancer models.

Main Results:

  • TR3 knockdown inhibited lung cancer cell growth and induced apoptosis.
  • TR3 promotes survival via a p300/TR3/Sp1 complex affecting survivin and Sp-regulated genes.
  • TR3 inhibition activated p53, induced sestrin 2, and inhibited the mTORC1 pathway via AMPKα activation.
  • DIM-C-pPhOH mimicked siTR3 effects, reducing tumor growth, inducing apoptosis, decreasing survivin, and inhibiting mTORC1 signaling.

Conclusions:

  • TR3's pro-oncogenic activity in lung cancer involves p53 inhibition and mTORC1 activation.
  • TR3 inactivation represents a novel therapeutic strategy for lung cancer.
  • TR3 inhibitors, like DIM-C-pPhOH, function as novel mTORC1 inhibitors, offering a new class of anti-cancer drugs.

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