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Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc

Ying-Nan Wang1,2, Dan-Yun Ruan2,3, Zi-Xian Wang1,2

  • 1Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.

Oncogene
|November 1, 2022
PubMed

Insights

Targeting the cholesterol-RORα/γ axis offers a novel strategy for colorectal cancer (CRC). Activating Retinoic acid receptor-related Orphan Receptor α/γ (RORα/γ) with agonists, combined with atorvastatin, shows promise for CRC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Cholesterol metabolism is dysregulated in colorectal cancer (CRC), but cholesterol-lowering agents show limited benefit.
  • The specific nuclear receptors (NRs) influenced by cholesterol in CRC progression remain unclear.

Purpose of the Study:

  • To investigate the role of the cholesterol-nuclear receptor (NR) axis in colorectal cancer (CRC).
  • To identify key NRs downstream of cholesterol involved in CRC progression.
  • To evaluate therapeutic strategies targeting this axis.

Main Methods:

  • CRC cells were treated with cholesterol-lowering agents and lipoprotein-depleted medium.
  • Changes in NR expression were analyzed.
  • RORα/γ agonists and atorvastatin were used in vitro and in vivo to assess effects on CRC cell proliferation and migration.
  • Mechanisms involving c-myc degradation and NEDD4 activation were investigated.

Main Results:

  • Cholesterol deprivation led to increased Retinoic acid receptor-related Orphan Receptor α/γ (RORα/γ) levels in CRC cells.
  • RORα/γ agonists inhibited CRC cell proliferation and migration, while RORα/γ knockdown promoted these processes.
  • RORα/γ agonists enhanced c-myc degradation by activating NEDD4 transcription.
  • Combination therapy with RORα/γ agonists and atorvastatin demonstrated synergistic inhibition of CRC cells.

Conclusions:

  • The cholesterol-RORα/γ axis is crucial for maintaining c-myc protein levels in CRC.
  • Targeting RORα/γ, particularly in combination with atorvastatin, represents a promising therapeutic strategy for colorectal cancer.

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