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Wogonin Induced Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Human Malignant Neuroblastoma Cells Via IRE1α-Dependent Pathway

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Abstract

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.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China

    Wenliang Ge, Qiyou Yin & Hua Xian

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  1. Wenliang Ge
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  2. Qiyou Yin
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  3. Hua Xian
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Correspondence to Qiyou Yin or Hua Xian.

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Ge, W., Yin, Q. & Xian, H. Wogonin Induced Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Human Malignant Neuroblastoma Cells Via IRE1α-Dependent Pathway. J Mol Neurosci 56, 652–662 (2015). https://doi.org/10.1007/s12031-015-0530-9

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  • DOI: https://doi.org/10.1007/s12031-015-0530-9

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