Open AccessFluoxetine induces autophagic cell death via eEF 2K‐ AMPK ‐ mTOR ‐ ULK complex axis in triple negative breast cancer
Author(s) -
Sun Dejuan,
Zhu Lingjuan,
Zhao Yuqian,
Jiang Yingnan,
Chen Lixia,
Yu Yang,
Ouyang Liang
Publication year - 2018
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12402
Subject(s) - autophagy , pi3k/akt/mtor pathway , ampk , programmed cell death , apoptosis , triple negative breast cancer , fluoxetine , mtt assay , transfection , viability assay , microbiology and biotechnology , chemistry , cancer research , cancer cell , biology , cancer , breast cancer , biochemistry , receptor , phosphorylation , protein kinase a , gene , genetics , serotonin
Objectives Triple negative breast cancer ( TNBC ) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small‐molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small‐molecule agent for TNBC treatment and illuminate its potential mechanisms. Materials and methods Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP ‐ LC 3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine‐induced autophagy and apoptosis. Western blotting and si RNA transfection were carried out to investigate the mechanisms of Fluoxetine‐induced autophagy. iTRAQ ‐based proteomics analysis was used to explore the underlying mechanisms. Results We have demonstrated that Fluoxetine had remarkable anti‐proliferative activities and induced autophagic cell death in MDA ‐ MB ‐231 and MDA ‐ MB ‐436 cells. The mechanism for Fluoxetine‐induced autophagic cell death was associated with inhibition of eEF 2K and activation of AMPK ‐ mTOR ‐ ULK complex axis. Further iTRAQ ‐based proteomics and network analyses revealed that Fluoxetine‐induced mechanism was involved in BIRC 6, BNIP 1, SNAP 29 and Bif‐1. Conclusions These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC , which will hold a promise for the future TNBC therapy.