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

Karin Von Schwarzenberg, Romina M. Wiedmann, Prajakta Oak, Sabine Schulz, Hans Zischka, Gerhard Wanner, Thomas Efferth, Dirk Trauner, Angelika M. Vollmar

Research output: Contribution to journalArticle

Abstract

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 led to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1α (HIF1α) and autophagy. Autophagy, which was demonstrated by degradation of p62 or fusion of autophagosomes with lysosomes, was induced at low concentrations of archazolid that not yet increase pH in lysosomes. HIF1α was induced due to energy stress shown by a decline of the ATP level and followed by a shutdown of energy-consuming processes. As silencing HIF1α 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 HIF1α 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.

Original languageEnglish (US)
Pages (from-to)1385-1396
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number2
DOIs
StatePublished - Jan 11 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Von Schwarzenberg, K., Wiedmann, R. M., Oak, P., Schulz, S., Zischka, H., Wanner, G., Efferth, T., Trauner, D., & Vollmar, A. M. (2013). Mode of cell death induction by pharmacological vacuolar H +-ATPase (V-ATPase) inhibition. Journal of Biological Chemistry, 288(2), 1385-1396. https://doi.org/10.1074/jbc.M112.412007