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.
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.
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