Decursin enhances TRAIL‐induced apoptosis through oxidative stress mediated‐ endoplasmic reticulum stress signalling in non‐small cell lung cancers

• Published in: British journal of pharmacology 2016-03, Vol.173 (6), p.1033-1044
• Main Authors: Kim, Jaekwang, Yun, Miyong, Kim, Eun‐Ok, Jung, Deok‐Beom, Won, Gunho, Kim, Bonglee, Jung, Ji Hoon, Kim, Sung‐Hoon
• Format: Article
• Language: English
• Subjects: Activating transcription factor 4; Activating Transcription Factor 4 - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzopyrans - pharmacology; Butyrates - pharmacology; Carcinoma, Non-Small-Cell Lung - metabolism; Cell death; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Cellular stress response; Drug Synergism; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Flow cytometry; Homology; Humans; Iodides; Kinases; Lung cancer; Lung Neoplasms - metabolism; Non-small cell lung carcinoma; Oxidative stress; Oxidative Stress - drug effects; Pancreas; Propidium iodide; Proteins; Reactive oxygen species; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Research Paper; Research Papers; Signal transduction; Signal Transduction - drug effects; Survivin; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL protein; Tumor cell lines; Tumor necrosis factor; Tumors; Western blotting
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13408

Background and Purpose The TNF‐related apoptosis‐inducing ligand (TRAIL) is a promising anticancer agent due to its remarkable ability to selectively kill tumour cells. However, because most tumours exhibit resistance to TRAIL‐induced apoptosis, the development of combination therapies to overcome resistance to TRAIL is required for effective cancer therapy. Experimental Approach Cell viability and possible synergy between the plant pyranocoumarin decursin and TRAIL was measured by MTT assay and calcusyn software. Reactive oxygen species (ROS) and apoptosis were measured using dichlorodihydrofluorescein and annexin/propidium iodide in cell flow cytometry. Changes in protein levels were assessed with Western blotting. Key Results Combining decursin and TRAIL markedly decreased cell viability and increased apoptosis in TRAIL‐resistant non‐small‐cell lung cancer (NSCLC) cell lines. Decursin induced expression of the death receptor 5 (DR5). Inhibition of DR5 attenuated apoptotic cell death in decursin + TRAIL treated NSCLC cell lines. Interestingly, induction of DR5 and CCAAT/enhancer‐binding protein homologues protein by decursin was mediated through selective induction of the pancreatic endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) branch of the endoplasmic reticulum stress response pathway. Furthermore, enhancement of PERK/ATF4 signalling by decursin was mediated by ROS generation in NSCLC cell lines, but not in normal human lung cells. Decursin also markedly down‐regulated expression of survivin and Bcl‐xL in TRAIL‐resistant NSCLC cells. Conclusions and Implications ROS generation by decursin selectively activated the PERK/ATF4 axis of the endoplasmic reticulum stress signalling pathway, leading to enhanced TRAIL sensitivity in TRAIL‐resistant NSCLC cell lines, partly via up‐regulation of DR5.