Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis. NAMPT protein is a secreted plasma biomarker in inflammation and in cancer. The NAMPT enzymatic inhibitor, FK866, acts as an inducer of apoptosis and is a cancer therapeutic candidate, however, little is known regarding the influence of NAMPT on cancer biological mechanisms or on the prognosis of human cancers. We interrogated known microarray data sets to define NAMPT knockdown-influenced gene expression to demonstrate that reduced NAMPT expression strongly dysregulates cancer biology signaling pathways. Comparisons of gene expression datasets of four cancer types generated a N39 molecular signature exhibiting consistent dysregulated expression in multiple cancer tissues. The N39 signature provides a significant and independent prognostic tool of human recurrence-free survival in lung and breast cancers. Despite the absence of clear elucidation of molecular mechanisms, this study validates NAMPT as a novel “oncogene” with a central role in carcinogenesis. Furthermore, the N39 signature provides a potentially useful tool for prediction of recurrence-free survival in lung and breast cancer and validates NAMPT as a novel and effective therapeutic target in cancer.
Highlights
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis
As an enzyme, intracellular NAMPT or iNAMPT is responsible for regeneration of intracellular NAD1, which is a multifunctional co-factor in many cellular events, such as transcriptional regulation, longevity and caloric-restriction responses, cell cycle progression, apoptosis, DNA repair, circadian rhythms, chromatin dynamics regulation, and telomerase activity, processes closely related to cancer pathogenesis[6]
Two independent microarray datasets containing gene expression information for both wild type and NAMPT-silenced cells were collected from the Gene Expression Omnibus (GEO) database[12]: one dataset was derived from a MCF-7 breast cancer cell line (GSE13449)[13] and the second dataset was from human pulmonary microvascular endothelial cells (GSE34512)[14]
Summary
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis. Pyrophosphate to yield nicotinamide mononucleotide, and is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) synthesis[1] This multifunctional enzyme was first cloned from human lymphocytes, and named pre-B cell colony-enhancing factor as a secreted cytokine[2]. We identified differentially expressed genes utilizing microarray data from two independent human cell lines (primary and cancer cells) and wild-type (WT) cells and NAMPT knock down (KD) cells These differentially-expressed genes were denoted as NAMPT-influenced genes with gene ontology analysis indicating enriched cancer-related pathways. Thirty-nine NAMPT-influenced genes were identified as being commonly differentially expressed in tumor tissues and comprised a multi-molecular cancer outcome predictor Our studies indicate this molecular signature effectively predicts recurrence-free survival in lung and breast cancer in a manner independent of standard clinical and pathological prognostic factors
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