Open AccessSphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A‐RIPK1‐dependent necroptosis
Author(s) -
Saddoughi Sahar A.,
Gencer Salih,
Peterson Yuri K.,
Ward Katherine E.,
Mukhopadhyay Archana,
Oaks Joshua,
Bielawski Jacek,
Szulc Zdzislaw M.,
Thomas Raquela J.,
Selvam Shanmugam P.,
Senkal Can E.,
GarrettMayer Elizabeth,
De Palma Ryan M.,
Fedarovich Dzmitry,
Liu Angen,
Habib Amyn A.,
Stahelin Robert V.,
Perrotti Danilo,
Ogretmen Besim
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201283
Subject(s) - necroptosis , ripk1 , ceramide , biology , programmed cell death , cancer research , microbiology and biotechnology , protein phosphatase 2 , sphingosine , chemistry , apoptosis , phosphatase , biochemistry , phosphorylation , receptor
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.