Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis

Sahar A. Saddoughi, Salih Gencer, Yuri K. Peterson, Katherine E. Ward, Archana Mukhopadhyay, Joshua Oaks, Jacek Bielawski, Zdzislaw M. Szulc, Raquela J. Thomas, Shanmugam P. Selvam, Can E. Senkal, Elizabeth Garrett-Mayer, Ryan M. De Palma, Dzmitry Fedarovich, Angen Liu, Amyn A. Habib, Robert V. Stahelin, Danilo Perrotti, Besim Ogretmen

Research output: Contribution to journalArticle

155 Scopus citations

Abstract

Mechanisms that alter protein phosphatase 2A (PP2A)-dependent lung tumour suppression via the I2PP2A/SET oncoprotein are unknown. We show here that the tumour suppressor ceramide binds I2PP2A/SET selectively in the nucleus and including its K209 and Y122 residues as determined by molecular modelling/simulations and site-directed mutagenesis. Because I2PP2A/SET was found overexpressed, whereas ceramide was downregulated in lung tumours, a sphingolipid analogue drug, FTY720, was identified to mimick ceramide for binding and targeting I2PP2A/SET, leading to PP2A reactivation, lung cancer cell death, and tumour suppression in vivo. Accordingly, while molecular targeting of I2PP2A/SET by stable knockdown prevented further tumour suppression by FTY720, reconstitution of WT-I2PP2A/SET expression restored this process. Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis. The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720. Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1-/- MEFs. Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1.

Original languageEnglish (US)
Pages (from-to)105-121
Number of pages17
JournalEMBO Molecular Medicine
Volume5
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Ceramide
  • FTY720
  • Sphingolipids
  • Sphingosine
  • Sphingosine kinase 2

ASJC Scopus subject areas

  • Molecular Medicine

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    Saddoughi, S. A., Gencer, S., Peterson, Y. K., Ward, K. E., Mukhopadhyay, A., Oaks, J., Bielawski, J., Szulc, Z. M., Thomas, R. J., Selvam, S. P., Senkal, C. E., Garrett-Mayer, E., De Palma, R. M., Fedarovich, D., Liu, A., Habib, A. A., Stahelin, R. V., Perrotti, D., & Ogretmen, B. (2013). Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Molecular Medicine, 5(1), 105-121. https://doi.org/10.1002/emmm.201201283