ReferenceID 1371
Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis
Pharmacol Res
Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treat
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- Reference Id
- 1371
- Evidence Id
- 17961
- Core Evidence Id
- 17961
- Source Reference Id
- 2759
- Herb2 Reference Id
- HBREF003556
- Subject Paper Key
- HBIN018930_34998973
- Pubmed Id
- 34998973
- Doi
- 10.1016/j.phrs.2022.106059
- Paper Title
- Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis
- Paper Abstract
- Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treating a wide range of tumors; however, the direct targets of Bru and its anticancer mode of action remain unclear. In our study, 793 Bru-binding candidate proteins were identified by using a biotin-brusatol conjugate (Bio-Bru) followed by streptavidin-affinity pull down-based mass spectrometry. We found that Bru can directly bind to Skp1 and disrupt the interactions of Skp1 with the F-box protein Skp2, leading to the inhibition of the Skp2-SCF E3 ligase. Bru inhibited both proliferation and migration via promoting the accumulation of the substrates p27 and E-cadherin; Skp1 overexpression attenuated while Skp1 knockdown enhanced these effects of Bru in non-small cell lung cancer (NSCLC) cells. Moreover, Bru binding to Skp1 also inhibited the β-TRCP-SCF E3 ligase. In both subcutaneous and orthotopic NSCLC xenografts, Bru significantly inhibited the growth and metastasis of NSCLC through targeting SCF complex and upregulating p27 and E-cadherin protein levels. These data demonstrate that Bru is a Skp1-targeting agent that may have therapeutic potentials in lung cancer.
- Journal
- Pharmacol Res
- Publish Year
- 2022
- Experiment Subject
- Experiment Type
- Animal Experiment
- Phenotype Related
- Tumors; Non-small Cell Lung Cancer; Lung Cancer; Cancer
- Paper Title Cn
- Paper Title En
- Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis
- Bilingual Status
- semi_complete