Open AccessCQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species
Author(s) -
Fu Zhiping,
Cheng Xi,
Kuang Jie,
Feng Haoran,
Chen Lingxie,
Liang Juyong,
Shen Xiaonan,
Yuen Stanley,
Peng Chenghong,
Shen Baiyong,
Jin Zhijian,
Qiu Weihua
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12179
Subject(s) - autophagy , apoptosis , reactive oxygen species , gemcitabine , cytotoxicity , chemistry , pancreatic cancer , cancer research , lysosome , programmed cell death , cancer cell , microbiology and biotechnology , pharmacology , biology , biochemistry , cancer , in vitro , enzyme , genetics
As an established anticancer drug, gemcitabine ( GEM ) is an effective systemic treatment for advanced pancreatic cancer ( PC ). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM . Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose‐dependent manner in PANC ‐1 and Bx PC ‐3 cells. Inhibition of autophagy by chloroquine ( CQ ) and ATG 7 si RNA increased GEM ‐induced cytotoxicity, and CQ was more effective than ATG 7 si RNA . Moreover, CQ significantly enhanced GEM ‐induced apoptosis, while ATG 7 si RNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species ( ROS ) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS . Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.