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

Li Ping Shu, Zhi Wei Zhou, Dan Zi, Zhi Xu He, Shu Feng Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2442-2461
Number of pages20
JournalAmerican Journal of Translational Research
Volume7
Issue number11
StatePublished - 2015
Externally publishedYes

Keywords

  • Alisertib
  • Apoptosis
  • Autophagy
  • Cell cycle
  • Human erythroleukemia cells
  • SILAC

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

Fingerprint

Dive into the research topics of 'A SILAC-based proteomics elicits the molecular interactome of alisertib (MLN8237) in human erythroleukemia K562 cells'. Together they form a unique fingerprint.

Cite this