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
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Mentions: To examine whether binding/targeting of I2PP2A/SET by FTY720 inhibits lung tumour growth via PP2A activation, we measured PP2A activity in response to shRNA-mediated I2PP2A knockdown (∼90%) in A549 cells (Fig 6A). Then, effects of WT-I2PP2A/SET reconstitution (∼60%) in A549/sh-I2PP2A/SET cells on PP2A activity in response to FTY720 was also measured compared to controls (Fig 6A). Interestingly, whereas FTY720 enhanced PP2A activity compared to vehicle-treated controls, knockdown of I2PP2A/SET also significantly enhanced PP2A activity, but prevented its further activation by FTY720 (Fig 6B). In contrast, when WT-I2PP2A/SET was restored in A549/sh-I2PP2A/SET cells, the PP2A activity was increased in response to FTY720 (Fig 6B). Thus, these data suggest that FTY720 activates PP2A via targeting I2PP2A/SET.
Affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.