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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (01))
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
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
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
Saddoughi, Sahar A; Ogretmen, Besim (2013) Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res 117:37-58
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
Meyers-Needham, Marisa; Ponnusamy, Suriyan; Gencer, Salih et al. (2012) Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells. EMBO Mol Med 4:78-92
Meyers-Needham, Marisa; Lewis, Jocelyn A; Gencer, Salih et al. (2012) Off-target function of the Sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide-dependent neutral sphingomyelinase 2/ceramide induction. Mol Cancer Ther 11:1092-102
Senkal, Can E; Ponnusamy, Suriyan; Manevich, Yefim et al. (2011) Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J Biol Chem 286:42446-58
Baran, Yusuf; Bielawski, Jacek; Gunduz, Ufuk et al. (2011) Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J Cancer Res Clin Oncol 137:1535-44

Showing the most recent 10 out of 30 publications