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Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt/mTOR‐independent pathway
Author(s) -
Zhao Xiaofang,
Luo Guosong,
Cheng Ying,
Yu Wenjing,
Chen Run,
Xiao Bin,
Xiang Yuancai,
Feng Chunhong,
Fu Wenguang,
Duan Chunyan,
Yao Fuli,
Xia Xianming,
Tao Qinghua,
Wei Mei,
Dai Rongyang
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26723
Subject(s) - autophagy , pi3k/akt/mtor pathway , protein kinase b , chemistry , ampk , microbiology and biotechnology , p38 mitogen activated protein kinases , phosphorylation , programmed cell death , kinase , protein kinase a , cancer research , signal transduction , biology , apoptosis , biochemistry
Abstract Compound C, a well‐known inhibitor of AMP‐activated protein kinase (AMPK), has been reported to exert antitumor activities in some types of cells. Whether compound C can exert antitumor effects in human cholangiocarcinoma (CCA) remains unknown. Here, we demonstrated that compound C is a potent inducer of cell death and autophagy in human CCA cells. Autophagy inhibitors increased the cytotoxicity of compound C towards human CCA cells, as confirmed by increased LDH release, and PARP cleavage. It is notable that compound C treatment increased phosphorylated Akt, sustained high levels of phosphorylated p70S6K, and decreased mTOR regulated p‐ULK1 (ser757). Based on the data that blocking PI3K/Akt or mTOR had no apparent influence on autophagic response, we suggest that compound C induces autophagy independent of Akt/mTOR signaling in human CCA cells. Further study demonstrated that compound C inhibited the phosphorylation of JNK and its target c‐Jun. Blocking JNK by SP600125 or siRNA suppressed autophagy induction upon compound C treatment. Moreover, compound C induced p38 MAPK activation, and its inhibition promoted autophagy induction via JNK activation. In addition, compound C induced p53 expression, and its inhibition attenuated compound C‐induced autophagic response. Thus, compound C triggers autophagy, at least in part, via the JNK and p53 pathways in human CCA cells. In conclusion, suppresses autophagy could increase compound C sensitivity in human CCA.