Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma

Abstract

Abstract CDK4 is highly expressed and correlated with poor prognosis and decreased survival in advanced NB. Seeking a regimen that selectively targets CDK4 degradation is a potentially promising therapeutic strategy relative to conventional CDK4 inhibitors.In this work, we determined that autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest and growth inhibition via the blockade of autophagy-related gene Beclin1. Secondly, we observed the first evidence that the p62 binds to CDK4 and then enter autophagolysosome to degradate CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Analogous results regarding the interaction p62 with CDK4 were observed in NVP-BEZ235 treated neuroblastoma xenograft mouse model. These results not only established the pivotal role of the autophagy pathway in CDK4 turnover but also suggest the potential application of NVP-BEZ235 or other drugs via the therapeutic modulation of autophagic degradation of CDK4 protein in NB.