FTY720 is a sphingosine analogue drug that has been recently approved by FDA for the treatment of patients with refractory multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), and P- FTY720 is immune suppressive, which is required for its anti-MS activity. This proposal was designed to test a novel hypothesis that FTY720, but not its immunesuppressive form P-FTY720, suppresses NSCLC tumor growth by directly targeting I2PP2A/SET oncoprotein, leading to activation of PP2A, RIPK1-dependent programmed necrosis (necroptosis) and consequent tumor suppression. To test this hypothesis, two Specific Aims are proposed:
Aim 1 was designed to determine the roles and mechanisms by which binding I2PP2A/SET by FTY720 activates tumor suppressive PP2A.
Aim 2 was designed to determine the down- stream mechanisms by which targeting I2PP2A/SET by FTY720 induces cell death.
The studies proposed in this application will help identify a novel molecular target, I2PP2A/SET oncoprotein, and they will provide a first-in-class treatment option using an already FDA-approved drug, FTY720, for selectively targeting I2PP2A/SET, leading to NSCLC tumor suppression via induction of programmed necrosis, providing a mechanism-based precision therapeutic strategy for the treatment of this disease.
|Dany, Mohammed; Gencer, Salih; Nganga, Rose et al. (2016) Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 128:1944-1958|
|Tirodkar, Tejas S; Lu, Ping; Bai, Aiping et al. (2015) Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner. J Biol Chem 290:13157-67|
|Dany, Mohammed; Ogretmen, Besim (2015) Ceramide induced mitophagy and tumor suppression. Biochim Biophys Acta 1853:2834-45|
|Panneer Selvam, Shanmugam; De Palma, Ryan M; Oaks, Joshua J et al. (2015) Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci Signal 8:ra58|
|Jiang, Wenhui; Ogretmen, Besim (2014) Autophagy paradox and ceramide. Biochim Biophys Acta 1841:783-92|
|Qin, Zhiqiang; Dai, Lu; Trillo-Tinoco, Jimena et al. (2014) Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther 13:154-64|
|Hamed, Hossein A; Das, Swadesh K; Sokhi, Upneet K et al. (2013) Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells. Cancer Biol Ther 14:1039-49|
|Alberg, Anthony J; Armeson, Kent; Pierce, Jason S et al. (2013) Plasma sphingolipids and lung cancer: a population-based, nested case-control study. Cancer Epidemiol Biomarkers Prev 22:1374-82|
|Saddoughi, Sahar A; Gencer, Salih; Peterson, Yuri K et al. (2013) Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 5:105-21|
|Oaks, Joshua J; Santhanam, Ramasamy; Walker, Christopher J et al. (2013) Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies. Blood 122:1923-34|
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