Open AccessBlocking autophagy enhances meloxicam lethality to hepatocellular carcinoma by promotion of endoplasmic reticulum stress
Author(s) -
Zhong Jingtao,
Dong Xiaofeng,
Xiu Peng,
Wang Fuhai,
Liu Ju,
Wei Honglong,
Xu Zongzhen,
Liu Feng,
Li Tao,
Li Jie
Publication year - 2015
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.12221
Subject(s) - autophagy , meloxicam , atg5 , endoplasmic reticulum , ampk , unfolded protein response , apoptosis , programmed cell death , chemistry , microbiology and biotechnology , pi3k/akt/mtor pathway , cancer research , pharmacology , biology , protein kinase a , phosphorylation , biochemistry
Objectives Meloxicam, a selective cyclooxygenase‐2 ( COX ‐2) inhibitor, has been demonstrated to exert anti‐tumour effects against various malignancies. However, up to now, mechanisms involved in meloxicam anti‐hepatocellular carcinoma effects have remained unclear. Materials and methods Cell viability and apoptosis were assessed by CCK ‐8 and flow cytometry. Endoplasmic reticulum ( ER ) stress and autophagy‐associated molecules were analysed by western blotting and immunofluorescence assay. GRP 78 and Atg5 knock‐down by si RNA or chemical inhibition was used to investigate cytotoxic effects of meloxicam treatment on HCC cells. Results We found that meloxicam led to apoptosis and autophagy in HepG2 and Bel‐7402 cells via a mechanism that involved ER stress. Up‐regulation of GRP 78 signalling pathway from meloxicam‐induced ER stress was critical for activation of autophagy. Furthermore, autophagy activation attenuated ER stress‐related cell death. Blocking autophagy by 3‐methyladenine (3‐ MA ) or Atg5 si RNA knock‐down enhanced meloxicam lethality for HCC by activation of ER stress‐related apoptosis. In addition, GRP 78 seemed to lead to autophagic activation via the AMPK – mTOR signalling pathway. Blocking AMPK with a chemical inhibitor inhibited autophagy suggesting that meloxicam‐regulated autophagy requires activation of AMPK . Conclusions Our results revealed that both ER stress and autophagy were involved in cell death evoked by meloxicam in HCC cells. This inhibition of autophagy to enhance meloxicam lethality, suggests a novel therapeutic strategy against HCC .