Inhibition of aurora a kinase by alisertib induces autophagy and cell cycle arrest and increases chemosensitivity in human hepatocellular carcinoma hepG2 cells

Qiaohua Zhu, Xinfa Yu, Zhi Wei Zhou, Chengyu Zhou, Xiao Wu Chen, Shu Feng Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Aurora A kinase represent a feasible target in cancer therapy. Objective: To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. Method: The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. Results: Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. Conclusion: Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells.

Original languageEnglish (US)
Pages (from-to)386-401
Number of pages16
JournalCurrent Cancer Drug Targets
Volume17
Issue number4
DOIs
StatePublished - May 1 2017
Externally publishedYes

Keywords

  • Alisertib
  • Aurora kinase A
  • Cell cycle
  • Hepatocellular carcinoma
  • HepG2 cells
  • Programmed cell death
  • Proteomics
  • SILAC

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Drug Discovery
  • Cancer Research

Fingerprint

Dive into the research topics of 'Inhibition of aurora a kinase by alisertib induces autophagy and cell cycle arrest and increases chemosensitivity in human hepatocellular carcinoma hepG2 cells'. Together they form a unique fingerprint.

Cite this