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Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR

Baoshi Yuan1, Kexin Shi1,2, Juanmin Zha3

  • 1Cambridge-Su Genomic Resource Center, Suzhou medical college of Soochow University, Suzhou, Jiangsu, 215123, China.

Cell Death & Disease
|January 21, 2023
PubMed

Insights

Novel nuclear receptor modulators targeting RARβ, PPARγ, LXRs, and Rev-Erba show promise in inhibiting osteosarcoma growth. These drugs, including LE135 and T0901317, work through the mTOR pathway, offering a new therapeutic strategy for this bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osteosarcoma is the most common primary bone cancer in children and adolescents.
  • Chemoresistance limits the effectiveness of current osteosarcoma treatments.
  • Nuclear receptors (NRs) are emerging as potential therapeutic targets in cancer treatment.

Purpose of the Study:

  • To identify novel therapeutic targets and drugs for osteosarcoma.
  • To investigate the efficacy of nuclear receptor modulators in inhibiting osteosarcoma cell proliferation and tumor growth.
  • To elucidate the molecular mechanisms underlying the anti-osteosarcoma effects of NR modulators.

Main Methods:

  • Drug screening of 29 chemicals targeting 17 NRs in osteosarcoma and osteoblast cell lines.
  • In vitro proliferation assays and in vivo tumor growth studies.
  • Transcriptomic analysis, immunoblotting, and gene knockout experiments to investigate signaling pathways.

Main Results:

  • Specific NR modulators (LE135, T0070907, T0901317, SR9011) inhibited osteosarcoma cell proliferation but not normal osteoblasts.
  • These modulators demonstrated dose-dependent effects and efficacy in vivo, enhancing doxorubicin's anti-tumor activity.
  • NR modulators regulate PI3K/AKT/mTOR and ERK/mTOR pathways, with DDIT4 identified as a key downstream target.

Conclusions:

  • Modulators of RARβ, PPARγ, LXRs, and Rev-Erba inhibit osteosarcoma growth in vitro and in vivo.
  • The mTOR signaling pathway is crucial for the anti-osteosarcoma effects of these NR modulators.
  • Targeting NRs represents a promising novel therapeutic strategy for osteosarcoma treatment.

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