Targeting the p27 E3 ligase SCF Skp2 results in p27and Skp2-mediated cell-cycle arrest and activation of autophagy

摘要: Decreased p27(Kip1) levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCF(Skp2) E3 ligase function, resulting enhanced p27 ubiquitination proteasome-mediated degradation. While proteasome inhibitors stabilize p27(Kip1), agents inhibiting may represent more directly targeted drugs with the promise efficacy reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered function vitro, induced specific accumulation p21 other substrates cells without activating heat-shock protein response. CpdA prevented incorporation Skp2 into ligase, G(1)/S cell-cycle arrest as well SCF(Skp2)- p27-dependent cell killing. This programmed death was caspase-independent, instead occurred activation autophagy. In models multiple myeloma, overcame resistance to dexamethasone, doxorubicin, melphalan, bortezomib, also acted synergistically this inhibitor. Importantly, active against patient-derived plasma both myeloid lymphoblastoid leukemia blasts, showed preferential activity neoplastic while relatively sparing marrow components. These findings provide rational framework for further development novel class antitumor agents.