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 #
5R01CA088932-12
Application #
8639487
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pelroy, Richard
Project Start
2000-12-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29403
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
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
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
Neviani, Paolo; Harb, Jason G; Oaks, Joshua J et al. (2013) PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest 123:4144-57
Saddoughi, Sahar A; Ogretmen, Besim (2013) Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res 117:37-58
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

Showing the most recent 10 out of 43 publications