Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA173687-04
Application #
9076632
Study Section
Special Emphasis Panel (ZRG1)
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403

  Publications

Panneer Selvam, Shanmugam; Roth, Braden M; Nganga, Rose et al. (2018) Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3. J Biol Chem 293:9784-9800
Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6
Thomas, Raquela J; Oleinik, Natalia; Panneer Selvam, Shanmugam et al. (2017) HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol Med 9:1030-1051
Gencer, Salih; Oleinik, Natalia; Kim, Jisun et al. (2017) TGF-? receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci Signal 10:
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
Dany, Mohammed; Ogretmen, Besim (2015) Ceramide induced mitophagy and tumor suppression. Biochim Biophys Acta 1853:2834-45
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
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
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
Jiang, Wenhui; Ogretmen, Besim (2014) Autophagy paradox and ceramide. Biochim Biophys Acta 1841:783-92

Showing the most recent 10 out of 16 publications