EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells
| العنوان: | EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells |
|---|---|
| المؤلفون: | Yao-Lan Li, Wen-Bo Chen, Qiu-Ying Liu, Dong-Lei Ma, Fang-Yuan Shao, Hao Xiao, Hong-Yu Li, Guo-Cai Wang, Nai-Sum Wong, Man-Mei Li, Wang Yifei, Sheng Wang, Guang-Xiong Zhou, Zhong Liu |
| المصدر: | Oncotarget |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 0301 basic medicine, Programmed cell death, Thioredoxin-Disulfide Reductase, MAP Kinase Kinase 4, Thioredoxin reductase, Uterine Cervical Neoplasms, Caspase 3, HL-60 Cells, Transfection, 03 medical and health sciences, Lactones, 0302 clinical medicine, Cell Line, Tumor, sesquiterpene lactone, Medicine, Humans, Protein kinase B, PI3K/AKT/mTOR pathway, Traditional medicine, Cell Death, business.industry, apoptosis, thioredoxin reductase, ROS, thioredoxin, Cell biology, XIAP, Enzyme Activation, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, Thioredoxin, business, K562 Cells, Reactive Oxygen Species, Sesquiterpenes, Research Paper |
| الوصف: | Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants and found to have potential anticancer activities. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. In this study, we observed that EM23, a natural SL, exhibited anti-cancer activity in human cervical cancer cell lines by inducing apoptosis as indicated by caspase 3 activation, XIAP downregulation and mitochondrial dysfunction. Mechanistic studies indicated that EM23-induced apoptosis was mediated by reactive oxygen species (ROS) and the knockdown of thioredoxin (Trx) or thioredoxin reductase (TrxR) resulted in a reduction in apoptosis. EM23 attenuated TrxR activity by alkylation of C-terminal redox-active site Sec498 of TrxR and inhibited the expression levels of Trx/TrxR to facilitate ROS accumulation. Furthermore, inhibition of Trx/TrxR system resulted in the dissociation of ASK1 from Trx and the downstream activation of JNK. Pretreatment with ASK1/JNK inhibitors partially rescued cells from EM23-induced apoptosis. Additionally, EM23 inhibited Akt/mTOR pathway and induced autophagy, which was observed to be proapoptotic and mediated by ROS. Together, these results reveal a potential molecular mechanism for the apoptotic induction observed with SL compound EM23, and emphasize its putative role as a therapeutic agent for human cervical cancer. published_or_final_version |
| تدمد: | 1949-2553 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::03166519e304d772da59814429b5bf61Test https://pubmed.ncbi.nlm.nih.gov/26758418Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....03166519e304d772da59814429b5bf61 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
|---|