Our preliminary data suggested to us a novel hypothesis that SK-2 generated S1P induces NSCLC growth via mediating hTERT/c-Myc oncogenic axis. As a corollary, we hypothesize that targeting SK-2/S1P induces hTERT degradation, leading to c-Myc inhibition and NSCLC tumor suppression without affecting telomere- replication function of hTERT. These novel hypotheses will be tested in two Specific Aims:
Aim 1. Determine the roles and mechanisms of SK-2/S1P in the regulation of hTERT stability.
Aim 2. Define the mechanisms by which SK-2/S1P regulates a non-canonical function of hTERT for c-Myc activation involved in controlling NSCLC tumor growth/proliferation. Data obtained from these studies will help dissect how SK2/S1P signaling is involved in selective regulation of a telomere-replication-independent (non-canonical) function of hTERT for, at least in part, inducing c-Myc oncogene, involved in NSCLC tumor growth and/or proliferation. Moreover, these studies will lead to the development of mechanism-based novel therapeutic strategies for improved NSCLC treatment to selectively inhibit oncogenic SK2/S1P/hTERT/c-Myc axis without affecting telomere-length regulation.

Public Health Relevance

The long-term goal of this proposal is to develop novel therapeutic strategies for the treatment of non-small cell lung cancers (NSCLC) via uncovering mechanisms involved in the regulation of non-canonical/telomere replication-independent functions of human telomerase reverse transcriptase (hTERT) by pro-survival sphingosine kinase-2/sphingosine 1-phosphate (SK-2/S1P) signaling for c-Myc oncogene activation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088932-15
Application #
9231393
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Witkin, Keren L
Project Start
2002-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2019-03-31
Support Year
15
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
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
Lv, Zongyang; Yuan, Lingmin; Atkison, James H et al. (2017) Domain alternation and active site remodeling are conserved structural features of ubiquitin E1. J Biol Chem 292:12089-12099
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
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
Dai, Lu; Plaisance-Bonstaff, Karlie; Voelkel-Johnson, Christina et al. (2014) Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells. PLoS One 9:e102314

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