Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis.
Bottom Line: 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.
Affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.Show MeSH
Related in: MedlinePlus
Mentions: Binding of I2PP2A/SET to ceramide in lung cancer cells might have clinical and biological significance. To define the clinical relevance of I2PP2A/SET-C18-ceramide in cancer pathogenesis, we measured I2PP2A/SET and C18-ceramide in tumour versus pathologically non-cancerous adjacent lung tissues obtained from 10 patients with NSCLC using Western blotting and immunohistochemistry (IHC; Fig 2A and B). Data showed that I2PP2A/SET is overexpressed in 70% (7/10, n = 10) of these tumours (Fig 2A), whereas C18-ceramide and CerS1 mRNA levels are decreased (∼50%) in the majority of tumours (8/10, n = 10) compared to non-cancerous lung tissues (Fig 2C and D, respectively). Importantly, at least 4 of 10 patients exhibited overexpression of I2PP2A/SET in combination with down-regulation of C18-ceramide in their lung tumours, suggesting that tumour suppressive ceramide/PP2A signalling is altered in these tumours (Fig 2C and D). However, C16-ceramide was significantly higher (∼1.8-fold, p < 0.01, n = 10) in tumour compared to non-cancerous lung tissues, and there were no significant changes in the levels of other ceramide species (Supporting Information Fig S5).
Affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.