Phytochemical library screening reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non–small cell lung cancer

Abstract

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome‐dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant‐derived Skp2 inhibitor, betulinic acid (BA), via high‐throughput structure‐based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2‐SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H‐bonds with residue Lys145, decreases its stability by disrupting Skp1‐Skp2 interactions, thereby inhibiting the Skp2‐SCF E3 ligase and promoting the accumulation of its substrates; that is, E‐cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2‐SCF E3 ligase and upregulating p27 and E‐cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.

Abstract

By screening a phytochemical library via high‐throughput molecular docking, we identified that betulinic acid is capable of binding to Skp2 at residue Lys145, leading to decreased protein stability of Skp2 and the accumulation of its substrate protein p27 and E‐cadherin. Betulinic acid significantly inhibited the proliferation and migration of NSCLC through downregulating Skp2 both in vitro and in vivo.