title: 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.
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.
  
  
  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.
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Xin-Shuang
authors.initials: XS
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.|Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Medical Management Service Center of Shandong Provincial Health and Family Planning Commission, Jinan 250014, P.R. China.
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Liu
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Cao
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: De-Guo
authors.initials: DG
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, P.R. China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Zhang
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D014415:Tunicamycin; C546842:MTOR protein, human; C531198:dactolisib
keywords: PI3K/AKT/mTOR signaling pathway; apoptosis; autophagy; endoplasmic reticulum stress; small cell lung cancer