title: Evodiamine, a plant alkaloid, induces calcium/JNK-mediated autophagy and calcium/mitochondria-mediated apoptosis in human glioblastoma cells.
abstract: Glioblastomas, the most common primary gliomas, are characterized by increased invasion and difficult therapy. Major clinical medicines for treating gliomas merely extend the survival time for a number of months. Therefore, development of new agents against gliomas is important. Autophagy, a process for degrading damaged organelles and proteins, is an adaptive response to environmental stress. However, the role of autophagy in glioblastoma development still needs to be further investigated. Evodiamine, a major alkaloid isolated from Evodia rutaecarpa Bentham, has various pharmacological activities, such as inhibiting tumor growth and metastatic properties. However, the effects of evodiamine on glioblastomas and their detailed molecular mechanisms and autophagy formation are not well understood. In this study, we observed that evodiamine induced dose- and time-dependent apoptosis in glioma cells. Blockade of calcium channels in endoplasmic reticulum (ER) significantly reduced evodiamine-induced cytosolic calcium elevation, apoptosis, and mitochondrial depolarization, which suggests that evodiamine induces a calcium-mediated intrinsic apoptosis pathway. Interestingly, autophagy was also enhanced by evodiamine, and had reached a plateau by 24h. Pharmacological inhibition of autophagy resulted in increased apoptosis and reduced cell viability. Inhibition of ER calcium channel activation also significantly reduced evodiamine-induced autophagy. Inactivation of c-Jun N-terminal kinases (JNK) suppressed evodiamine-mediated autophagy accompanied by increased apoptosis. Furthermore, evodiamine-mediated JNK activation was abolished by BAPTA-AM, an intracellular calcium scavenger, suggesting that evodiamine mediates autophagy via a calcium-JNK signaling pathway. Collectively, these results suggest that evodiamine induces intracellular calcium/JNK signaling-mediated autophagy and calcium/mitochondria-mediated apoptosis in glioma cells.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Ann-Jeng
authors.initials: AJ
authors.lastname: Liu
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Wang
authors.forename: Ku-Chung
authors.initials: KC
authors.lastname: Chen
authors.forename: Hsiu-Ping
authors.initials: HP
authors.lastname: Kuei
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Shih
authors.forename: Sz-Ying
authors.initials: SY
authors.lastname: Hou
authors.forename: Wen-Ta
authors.initials: WT
authors.lastname: Chiu
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Chwen-Ming
authors.initials: CM
authors.lastname: Shih
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D032086:Evodia; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D011799:Quinazolines; C049639:evodiamine; D002118:Calcium
keywords: 2-APB; 2-aminoethoxydiphenyl borate; 3-MA; 3-methyladenine; 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazol-carbocyanine iodide; AIF; AVO; Apoptosis; Autophagy; Evo; Evodiamine; FITC; Intracellular calcium; JC-1; LC3; Malignant glioma; Mitochondria; PI; ROS; [Ca(2+)](i); acidic vesicular organelle; apoptosis-inducing factor; evodiamine; fluorescein isothiocyanate; intracellular calcium; microtubule-associated protein 1 light chain 3; propidium iodide; reactive oxygen species