title: Costunolide induces lung adenocarcinoma cell line A549 cells apoptosis through ROS (reactive oxygen species)-mediated endoplasmic reticulum stress.
abstract: Costunolide is an active sesquiterpene lactone derived from many herbal medicines. It has a broad spectrum of bioactivities, including anti-inflammatory and potential anti-tumor effects. The aims of the present study were to evaluate the inhibitory effects of costunolide on A549 cell growth and to explore the underlying molecular mechanisms. Annexin V-FITC/PI flow cytometry analysis revealed that costunolide induced apoptosis. To study the mechanism, we found that costunolide exposure activated the unfolded protein response (UPR) signaling pathways, as shown by the up-regulation of GRP78 and IRE1α and the activation of ASK1 and JNK. Meanwhile, siRNA knockdown of IRE1α significantly attenuated costunolide-induced apoptosis and partly restored the mitochondrial membrane potential. ER stress-activated JNK phosphorylated Bcl-2 at Ser70, which changes the anti-apoptotic function of Bcl-2, resulting in mitochondrial dysfunction and leading to mitochondrial activation of apoptosis. Furthermore, costunolide induced ROS generation, while the antioxidant N-acetyl cysteine (NAC) effectively blocked ER stress and apoptosis activation, suggesting that ROS acts as an upstream signaling molecule in triggering ER stress and mitochondrial apoptotic pathways. Taken together, our research demonstrates that costunolide exhibits its anti-tumor activity though inducing apoptosis, which is mediated by ER stress. We further confirm that Bcl-2 is a key molecule connecting the ER stress and mitochondrial pathways.
authors.affiliation: Institute of Biochemistry, Zhejiang University, Room 345, Hangzhou, 310058, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Biochemistry, Zhejiang University, Room 345, Hangzhou, 310058, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Biochemistry, Zhejiang University, Room 345, Hangzhou, 310058, PR China.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Gong
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000633:toxicity*; D007783:Lactones
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D048031:JNK Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C000717247:HSPA5 protein, human; C002602:costunolide; D007783:Lactones; C528229:ERN1 protein, human
keywords: apoptosis; costunolide; endoplasmic reticulum stress; mitochondrial apoptotic pathway; reactive oxygen species (ROS)