Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway

// Xin-Shuang Yu 1 , Juan Du 1, 2 , Yu-Jun Fan 3 , Feng-Jun Liu 1 , Li-Li Cao 2 , Ning Liang 1 , De-Guo Xu 1 , Jian-Dong Zhang 1 1 Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China 2 Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China 3 Medical Management Service Center of Shandong Provincial Health and Family Planning Commission, Jinan 250014, P.R. China Correspondence to: Jian-Dong Zhang, email: zh_jiand@yeah.net Juan Du, email: juanDU_sddx@126.com Keywords: endoplasmic reticulum stress, PI3K/AKT/mTOR signaling pathway, small cell lung cancer, autophagy, apoptosis Received: June 21, 2016      Accepted: September 28, 2016      Published: October 18, 2016 ABSTRACT Objective: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. Results: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h. Compared with the blank group, the tunicamycin, BEZ235 and tunicamycin + BEZ235 groups exhibited decreased expressions of p-PI3K, p-AKT and p-mTOR, and increased expressions of autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis proteins (Bax and procaspase-3), and the most obvious changes were observed in the tunicamycin + BEZ235 group. Materials and Methods: CCK-8 assay was applied to select the best cell line from five SCLC cell lines (NCI-H446, H69, H526, H146 and H209). Finally, NCI-H446 and H69 cells were selected for further experiments. NCI-H446/CDDP and H69/CDDP were selected and divided into the blank group, tunicamycin (an ESR inducer) group, BEZ235 (inhibitors of PI3K/AKT/mTOR pathway) group and tunicamycin + BEZ235 group. Cell apoptosis was detected by flow cytometry. Autophagy was observed by fluorescence microscopy and flow cytometry. Western blotting was used to detect the expressions of ERS-related proteins, autophagy-related proteins, apoptosis-related proteins and PI3K/AKT/mTOR pathway-related proteins. Conclusions: Our findings provide evidence that the activation of ERS could promote autophagy and apoptosis and reverse chemoresistance of human SCLC cells by inhibiting the PI3K/AKT/mTOR pathway.