Targeting Skp2 by camptothecin induces p27 accumulation and confers drug resistance in non-small cell lung cancer.

Skp2 plays a critical role in regulating cell cycle progression by promoting the ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27. Numerous studies have implicated Skp2 overexpression in cancer chemoresistance; however, its impact on sensitivity to camptothecin (CPT), a clinical topoisomerase I inhibitor, in non-small cell lung cancer (NSCLC) remains unclear. In this study, we identified that CPT can markedly induce the accumulation of p27. Mechanistically, CPT can directly bind to Skp2 protein and inhibit Skp2-SCF E3 ubiquitin ligase activity, as evidenced by decreased p27 ubiquitination level upon CPT treatment. Ectopic Skp2 expression in NSCLC cells abrogated CPT-induced p27 accumulation. Of note, Skp2 overexpression markedly increased CPT-induced DNA damage and apoptosis in NSCLC cells, and pharmacologic inhibition of Skp2 with SZL P1-41 partially reversed the cytotoxicity of CPT. Skp2-overexpressing A549 cell xenografts were also more sensitive to CPT than A549 cell xenografts with empty vector; tumors with high Skp2 levels exhibited lower p27 expression and greater DNA damage after CPT treatment. Collectively, our study demonstrated that the CPT induces p27 accumulation by targeting Skp2, whereas Skp2 overexpression can modulate the off-target effects and enhance CPT sensitivity in NSCLC, supporting the potential use of Skp2 as a predictive biomarker for CPT-based therapy.