Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid

Shiv K. Singh, Sandra Baumgart, Garima Singh, Alexander O. König, Kristina Reutlinger, Lorenz C. Hofbauer, Peter Barth, Thomas M. Gress, Gwen Lomberk, Raul Urrutia, Martin E. Fernandez-Zapico, Volker Ellenrieder

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19 Scopus citations

Abstract

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3&bete;-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

Original languageEnglish (US)
Pages (from-to)28761-28771
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number33
DOIs
StatePublished - Aug 19 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Singh, S. K., Baumgart, S., Singh, G., König, A. O., Reutlinger, K., Hofbauer, L. C., Barth, P., Gress, T. M., Lomberk, G., Urrutia, R., Fernandez-Zapico, M. E., & Ellenrieder, V. (2011). Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid. Journal of Biological Chemistry, 286(33), 28761-28771. https://doi.org/10.1074/jbc.M110.197533