Pregnenolone, a cholesterol metabolite, induces glioma cell apoptosis via activating extrinsic and intrinsic apoptotic pathways

Xiao,Xiao; Chen,Lijun; Ouyang,Ying; Zhu,Wenbo; Qiu,Pengxin; Su,Xinwen; Dou,Yunling; Tang,Lipeng; Yan,Min; Zhang,Haipeng; Yang,Xiaoxiao; Xu,Dong; Yan,Guangmei

doi:10.3892/ol.2014.2147

Pregnenolone, a cholesterol metabolite, induces glioma cell apoptosis via activating extrinsic and intrinsic apoptotic pathways

Authors:
- Xiao Xiao
- Lijun Chen
- Ying Ouyang
- Wenbo Zhu
- Pengxin Qiu
- Xinwen Su
- Yunling Dou
- Lipeng Tang
- Min Yan
- Haipeng Zhang
- Xiaoxiao Yang
- Dong Xu
- Guangmei Yan
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Affiliations: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Neonatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China, Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: May 16, 2014 https://doi.org/10.3892/ol.2014.2147
Pages: 645-650

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Abstract

Gliomas are one of the most common types of malignant tumors worldwide, however, an effective therapeutic strategy not yet been fully determined. The present study aimed to investigate the anti‑glioma activity and underlying mechanisms of pregnenolone, which originates from cholesterol and is metabolized into important steroid hormones in the body. The results demonstrated that 100 µM pregnenolone induced a significant loss of cell viability in various malignant glioma cell lines. In the U‑87 MG, LN‑18 and C6 cell lines, the loss of cell viability resulted from cell apoptosis, which was evidenced by apoptotic nuclear morphology changes and caspase 3 activation. Moreover, the increased activities of caspase 8 and 9 strongly indicated that pregnenolone activated the extrinsic and intrinsic pathways of apoptosis. Additionally, glioma cell apoptosis was prevented by the general caspase inhibitor, Z‑VAD‑FMK. In the C6 cells, upregulation of Fas and Fas ligand triggered the activation of the extrinsic pathway, whereas knockdown of Fas significantly abrogated the cell apoptosis that was induced by pregnenolone. Furthermore, downregulation of the anti‑apoptotic protein, B‑cell lymphoma 2 and upregulation of pro‑apoptotic proteins, such as Bax and Bak, activated the intrinsic pathway. In conclusion, pregnenolone induced glioma cell apoptosis in a caspase‑dependent manner, which was mediated by activation of the extrinsic and intrinsic apoptotic pathways.

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