The role of nicotinamide phosphoribosyltransferase (NAMPT) for oncogenic MYC functions and tumor-stroma crosstalk

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Deregulation of the proto-oncogene c-MYC and its product, the MYC protein, has been implicated in the genesis of the majority of cancers. We recently identified a positive feedback loop, in which MYC activates nicotinamide phosphoribosyltransferase (NAMPT) which enhances SIRT1 function and thereby increases MYC activity. NAMPT is the rate limiting enzyme of NAD+ salvage pathway and regulates the activity of the NAD+-dependent deacetylase SIRT1, thereby promoting cellular survival. The overall goal of this proposal is to establish the tumor biological relevance of the connection between MYC, NAMPT and SIRT1 using functional in vitro assays and a MYC-driven lymphoma mouse model. Furthermore, we will determine whether eNAMPT has a paracrine function in the tumor microenvironment. To achieve these goals, four approaches will be used: 1. The MYC-mediated up-regulation of NAMPT and SIRT1 will be analyzed in colorectal cancer samples to establish correlations with clinical parameters, such as progression, survival and metastasis. 2. The role of NAMPT for MYC functions such as induction of cell cycle progression, immortalization, transformation, glycolysis and gene regulation will be studied using conditional MYC alleles in human and mouse fibroblasts. 3. The role of NAMPT for MYC-induced lymphomas will be analyzed using a CD19-Cre-mediated B cell-specific deletion of one NAMPT allele in the Eµ-Myc model. We will also evaluate the effect of pharmacological inhibition of NAMPT for prevention and therapy of Eµ-Myc lymphomas. 4. Secreted, extracellular NAMPT (eNAMPT) acts in a cytokine-like fashion, conveying anti-apoptotic and growth signals. Elevated serum levels in cancer patients and secretion by cancer cell lines suggest that cancer cells may represent a possible source for eNAMPT. Here we will determine the function of tumor-released eNAMPT in colorectal cancer cell lines, and measure eNAMPT in serum of Eµ-Myc mice. We will address whether eNAMPT secretion is regulated by MYC, whether (e)NAMPT has the capacity to induce migration and invasion in vitro, and affects metastasis of colorectal cancer cell lines in xenografts assays. In summary, these studies will contribute to the understanding of intra- and extracellular NAMPT function in physiological and patho-physiological settings, as oncogenic activation of MYC. These studies may establish eNAMPT as a novel mediator of a metabolic crosstalk in cancer, and evaluate the potential of eNAMPT as a diagnostic marker. Furthermore, the detailed knowledge about the regulatory connections between MYC, NAMPT and SIRT1 in tumor progression may allow the development of innovative tumor therapeutic approaches in the future.