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

Background CDK4 is highly expressed and associated with poor prognosis and decreased survival in advanced neuroblastoma (NB).Targeting CDK4 degradation presents a potentially promising therapeutic strategy compared to conventional CDK4 inhibitors.However, the autophagic degradation of the CDK4 protein and its anti-proliferation effect in NB cells has not been mentioned.Results We identified autophagy as a new pathway for the degradation of CDK4.

Firstly, Crochet Flowers autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest, as demonstrated by the overexpression of CDK4, autophagy inhibition, and blockade of autophagy-related genes.Secondly, we present the first evidence that p62 binds to CDK4 and then enters the autophagy-lysosome to degrade CDK4 in a Coffee Mug CTSB-dependent manner in NVP-BEZ235 treated NB cells.Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model.Conclusions Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.

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