A SILAC-based proteomics elicits the molecular interactome of alisertib (MLN8237) in human erythroleukemia K562 cells

American Journal of Translational Research

Li-Ping Shu¹ 

关键词: Alisertib;    human erythroleukemia cells;    cell cycle;    apoptosis;    autophagy;    SILAC;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

Alisertib (MLN8237, ALS), an Aurora kinase A (AURKA) inhibitor, exerts potent anti-tumor effects in the treatment of solid tumor and hematologic malignancies in preclinical and clinical studies. However, the fully spectrum of molecular targets of ALS and its anticancer effect in the treatment of chronic myeloid leukemia (CML) are not clear. This study aimed to examine the proteomic responses to ALS treatment and unveil the molecular interactome and possible mechanisms for its anticancer effect in K562 cells using stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data identified that ALS treatment modulated the expression of 1541 protein molecules (570 up; 971 down). The pathway analysis showed that 299 signaling pathways and 459 cellular functional proteins directly responded to ALS treatment in K562 cells. These targeted molecules and signaling pathways were mainly involved in cell growth and proliferation, cell metabolism, and cell survival and death. Subsequently, the effects of ALS on cell cycle distribution, apoptosis, and autophagy were verified. The flow cytometric analysis showed that ALS significantly induced G2/M phase arrest and the Western blotting assays showed that ALS induced apoptosis via mitochondria-dependent pathway and promoted autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways in K562 cells. Collectively, this study provides a clue to quantitatively evaluate the proteomic responses to ALS and assists in globally identifying the potential molecular targets and elucidating the underlying mechanisms of ALS for CML treatment, which may help develop new efficacious and safe therapies for CML treatment.

【 授权许可】

CC BY-NC