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Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes

Qing Yu1, Zhiguo Hu2, Yanwen Shen1

  • 1Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Neoplasia (New York, N.Y.)
|March 8, 2020
PubMed

Insights

Gossypol inhibits cullin neddylation, a key process for cancer-driving E3 ligases. This natural compound targets CUL5 and CUL1, leading to cancer cell death and offering a new anticancer strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cullin-RING E3 ligases (CRLs) ubiquitylate ~20% of cellular proteins and are crucial in biological processes.
  • Abnormal CRL activation is implicated in cancer, necessitating targeted interventions.
  • CRL activation depends on neddylation, the attachment of NEDD8 to cullins, making it an attractive anticancer target.

Purpose of the Study:

  • To establish a high-throughput screening assay for CUL5 neddylation.
  • To identify small molecules that inhibit cullin neddylation.
  • To investigate the anticancer mechanism of identified inhibitors.

Main Methods:

  • Developed an Alpha-Screen-based high-throughput screen (HTS) for in vitro CUL5 neddylation.
  • Screened a library of 17,000 compounds, including FDA-approved drugs and natural products.
  • Conducted biochemical and cellular assays to validate inhibitor activity and mechanism.

Main Results:

  • Identified gossypol, a natural compound, as a potent inhibitor of cullin neddylation.
  • Gossypol directly binds to SAG-CUL5 and RBX1-CUL1 complexes, inhibiting neddylation of CUL5 and CUL1.
  • Gossypol treatment caused selective accumulation of NOXA and MCL1 (CRL substrates) in cancer cells.
  • Combination therapy of gossypol and an MCL1 inhibitor synergistically suppressed cancer cell growth.

Conclusions:

  • Gossypol exhibits a novel anticancer mechanism by inhibiting cullin neddylation.
  • Gossypol's ability to modulate CRL substrate levels presents a new therapeutic avenue.
  • This study highlights the potential of developing new neddylation inhibitors for cancer treatment.
Keywords:
Cullin-RING E3 ligaseGossypolNeddylationSmall molecule inhibitorsUbiquitin–proteasome system

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