Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells.
This study investigates the anticancer effect of dehydrocostuslactone (DHE), a medicinal plant-derived sesquiterpene lactone, on human non-small cell lung cancer cell lines, A549, NCI-H460 and NCI-H520. Our results show that DHE inhibits the proliferation of A549, NCI-H460 and NCI-H520 cells. DHE-induced apoptosis in both A549 and NCI-H460 cells. DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, PKR-like ER kinase (PERK) phosphorylation, inositol requiring protein 1 (IRE1) and CHOP/GADD153 upregulation, X-box transcription factor-1 (XBP-1) mRNA splicing, and caspase-4 activation. The release of calcium triggered the production of ROS, which further enhances calcium overloading and subsequently activates p38, JNK and ERK1/2. Both IRE1 miRNA transfection and BAPTA-AM pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. Importantly, a novel anticancer agent for the treatment of non-small cell lung cancer, and is supported by animal studies which have shown a dramatic 50% reduction in tumor size after 28 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of non-small cell lung cancer.
Hung
Jen-Yu
JY
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hsu
Ya-Ling
YL
Ni
Wen-Chiu
WC
Tsai
Ying-Ming
YM
Yang
Chih-Jen
CJ
Kuo
Po-Lin
PL
Huang
Ming-Shyan
MS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
D002118:Calcium; D053471:Caspases, Initiator; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D007783:Lactones; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D012717:Sesquiterpenes; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C083030:dehydrocostus lactone; C403982:ERN2 protein, human; C093516:CASP4 protein, human