18α-Glycyrrhetinic acid lethality for neuroblastoma cells via de-regulating the Beclin-1/Bcl-2 complex and inducing apoptosis

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• 作者：Md. Ataur Rahman¹ ; Kausik Bishayee¹ ; Khadija Habib ; Ali Sadra ; Sung-Oh Huh ; ^{sungohhuh@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; ^{s0huh@hallym.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Beclin-1 ; Macro-autophagy ; Apoptosis ; MAP kinase pathway ; Mitochondria membrane potential
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：117
• 期：Complete
• 页码：97-112
• 全文大小：5929 K

文摘

18α-Glycyrrhetinic acid (18-GA) is a known gap-junction inhibitor with demonstrated anticancer effects. However, the different modes of cell cytotoxicity for 18-GA remain to be characterized. In this study, 18-GA reduced the expression of cell-cell interaction proteins (N- and VE-cadherin), and led to a dose-dependent increase in cytotoxicity of the neuroblastoma cells tested, but was less toxic toward actively dividing human embryonic kidney cells. We found that 18-GA could induce both autophagy and apoptosis. 18-GA mediated autophagy was due to accumulation of Atg5, Atg7 and LC3II and degradation of p62. Individual siRNAs against Atg5 and Atg7 prevented autophagy and resulted in a further loss of viability with 18-GA. In addition, combination of 18-GA with autophagy inhibitor chloroquine produced a more significant cell death. This implied a pro-survival function for autophagy induction with 18-GA. 18-GA also led to the destabilization of Bcl-2/Beclin-1 interaction and cleavage of Beclin-1, a protein known to play role in apoptosis and autophagy induction. Treatment of cells by a pan-caspase inhibitor or a caspase-3 siRNA prevented a large portion of 18-GA mediated cytotoxicity, demonstrating that caspase-dependent apoptosis induction was responsible for most of the observed cytotoxicity. In terms of signaling, 18-GA led to reduced phosphorylation of all three classes of MAP kinases. Taken together, 18-GA or its pathways may lead to more effective, targeted therapeutics against neuroblastoma.