Wogonin Induced Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Human Malignant Neuroblastoma Cells Via IRE1α-Dependent Pathway.
Wogonin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been reported to exhibit a variety of biological effects including anti-cancer effects. It has a pro-apoptotic role in many cancer types. However, the molecular mechanisms of wogonin in treating neuroblastoma remain elusive. In the present study, two malignant neuroblastoma cell lines (SK-N-BE2 and IMR-32 cells) were treated with different doses of wogonin (0-150 μM). Wogonin showed significant cytotoxic effects in SK-N-BE2 and IMR-32 cells in a dose- and time-dependent manner. Treatment of SK-N-BE2 and IMR-32 cells with 75 μΜ wogonin for 48 h significantly promoted apoptosis, the release of cytochrome c, altered the expression of certain members of Bcl-2 family (Bcl-2, Bax and Bid), and increased the activation of caspase-3, caspase-8, caspase-9, and PARP-1, which demonstrated that the cytotoxic effect of wogonin in SK-N-BE2 and IMR-32 cells is mediated by mitochondrial dysfunction. Moreover, wogonin induced the expression of endoplasmic reticulum (ER) stress-related proteins (GRP78/Bip and GRP94/gp96) and activation of caspase-12 and caspase-4 in SK-N-BE2 and IMR-32 cells. In addition, wogonin increase the expression of IRE1α and TRAF2, and phosphorylation of ASK1 and JNK in SK-N-BE2 and IMR-32 cells. Knockdown of IRE1α by siRNA not only markedly inhibited wogonin-induced up-regulation of IRE1α and TRAF2, and phosphorylation of ASK1 and JNK but also reduced wogonin-induced cytotoxic effects and mitochondrial dysfunction in SK-N-BE2 and IMR-32 cells. These results indicated that wogonin could induce apoptosis, mitochondrial dysfunction, and ER stress in SK-N-BE2 and IMR-32 cells by modulating IRE1α-dependent pathway.
Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
Wenliang
W
Ge
Qiyou
Q
Yin
Hua
H
Xian
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D044950:Flavanones / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D044950:Flavanones; C000717247:HSPA5 protein, human; D047992:TNF Receptor-Associated Factor 2; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases; C085514:wogonin