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

EMBO Molecular Medicine

Sahar A. Saddoughi¹  Salih Gencer¹  Yuri K. Peterson⁴  Katherine E. Ward³  Archana Mukhopadhyay¹  Joshua Oaks²  Jacek Bielawski¹  Zdzislaw M. Szulc¹  Raquela J. Thomas¹  Shanmugam P. Selvam¹  Can E. Senkal¹  Elizabeth Garrett-Mayer⁴  Ryan M. De Palma¹  Dzmitry Fedarovich¹  Angen Liu⁴  Amyn A. Habib⁵  Robert V. Stahelin³  Danilo Perrotti² 

[1] Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA;Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA;Department of Chemistry and Biochemistry and the Mike and Josie Harper Center for Cancer Research, University of Notre Dame, Notre Dame, IN, USA;Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA

关键词: ceramide;    FTY720;    sphingolipids;    sphingosine;    sphingosine kinase 2;   

DOI  :  10.1002/emmm.201201283

来源: Wiley

【 摘 要 】

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.

【 授权许可】

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