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Mode of cell death induction by pharmacological vacuolar H+-ATPase (V-ATPase) inhibition

dr.qinan 添加于 2012-12-7 21:01 | 2459 次阅读 | 0 个评论

作者
von Schwarzenberg K, Wiedmann RM, Oak P, Schulz S, Zischka H, Wanner G, Efferth T, Trauner D, Vollmar AM
摘要
The vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump, has come into focus as an attractive target in cancer invasion. However little is known about the role of V-ATPase in cell death and especially the underlying mechanisms remain mostly unknown. We used the myxobacterial macrolide archazolid B, a potent inhibitor of the V-ATPase, as an experimental drug as well as a chemical tool to decipher V-ATPase related cell death signaling. We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway. Prior to apoptosis induction archazolid lead to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1 alpha (HIF1alpha) and autophagy. Autophagy was induced at low concentrations of archazolid that do not alter pH in lysosomes and was shown by degradation of p62 or fusion of autophagosomes with lysosomes. HIF1alpha was induced due to energy stress shown by a decline of the ATP level and followed by a shut down of energy consuming processes. As silencing HIF1alpha increases apoptosis, the cellular stress response was suggested to be a survival mechanism. We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1alpha and finally leads to apoptosis. We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis, autophagy and cellular/metabolic stress.
详细资料
- 文献种类:期刊
- 期刊名称: The Journal of Biological Chemistry
- 期刊缩写: J Biol Chem
- 期卷页: 2012年
- 地址: LMU Munich, Germany
- ISBN: 0021-9258
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