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.

Silybin has therapeutic efficacy against non-small cell lung cancer through targeting of Skp2

“…Molecular docking simulations were performed as previously described [6]. In brief, the three-dimensional structure of SB (Pubchem) and the crystal structure of the Skp2-Skp1 complex (Protein Data Bank ID: 2AST) were prepared with the OpenBabel and AutoDock Tools, respectively.…”

“…Skp2 interacts with Skp1 and forms two binding pockets around the F-box motif in Skp2, thus facilitating drug targeting [4]. Compounds such as betulinic acid and compound #25 (SZL P1-41), directly bind Skp2 and hinder Skp1-Skp2 interaction [5,6]. These Skp2 inhibitors abrogate proteolytic ubiquitination of p27 and E-cadherin, as well as non-proteolytic ubiquitination and phosphorylation of Akt, thereby inhibiting cell-cycle progression, tumor metastasis, glycolysis, and cancer stemness [5].…”

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

“…Among the developed selective small molecular inhibitors of Skp2, mechanisms through which different inhibitors exert their antitumor effects by inhibiting the activity of the Skp2 E3 ligase are different [ 173 , 215 ]. For example, Compound A blocks the assembly of Skp2 in the SCF complex [ 175 ]; C1, C2, C16, and C20 inhibit p27 ubiquitination by targeting the binding interface between Skp2–Cks1 and p27 [ 176 ]; Compound 25 inhibits the formation of the Skp2–Skp1 complex [ 177 ]; DT204 reduces Skp2 binding to Cullin-1 and Commd1 (Cullin-1 binding protein) [ 178 ]; and betulinic acid binds to Skp2, reducing its stability and the accumulation of its substrate protein [ 179 ]. Dioscin may be a promising multitarget drug candidate for treating various tumors and exerts an immunomodulatory effect [ 216 ].…”

A Ubiquitin-Proteasome Gene Signature for Predicting Prognosis in Patients With Lung Adenocarcinoma

“…In fact, the UPS is already an important target in various cancer treatments, including the use of proteasome and ubiquitin E3 ligases as therapeutic targets for various chemotherapies ( Manasanch and Orlowski, 2017 ). Abnormal expression of different UPS gene families alters proteolysis, inhibiting the proliferation and metastasis of LUAD ( He et al, 2021 ). Thus, evaluating the relationship between UPS and tumorigenesis might provide novel insights into LUAD pathology and facilitate better patient prognosis.…”