Nampt/PBEF/visfatin is the rate-limiting enzyme that catalyzes the first step in NAD biosynthesis from nicotinamide and regulates growth, apoptosis and angiogenesis of mammalian cells. This enzyme was originally cloned as a putative cytokine shown to enhance the B cell precursor maturation in the presence of IL-7 and stem cell factor. A number of cancers have increased expression of Nampt/PBEF/visfatin, which regulates a variety of different signaling pathways such as PI3K/Akt, ERK1/2 and STAT3. FK866/APO866 and CHS828/GMX1777 are two known inhibitors of Nampt/PBEF/visfatin and have been evaluated as anticancer agents in the clinic. This review will focus on its role in carcinogenesis and cancer progression and its inhibitors as therapeutic target for cancer treatment.

Abstract. Nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the NAD + salvage pathway, is overexpressed and important in the carcinogenesis in several types of cancers. The expression of Nampt and its role in gastric cancer remain largely unknown. In this study, using real-time PCR and Western blotting we found that Nampt was overexpressed at the mRNA and protein levels, respectively, in established gastric cancer cells and human gastric cancer tissues. The specific Nampt inhibitor FK866 repressed gastric cancer cell proliferation, as assessed by MTT assay. Using transwell and soft agar clonogenic assays, we also found that FK866 suppressed gastric cancer cell migration and anchorageindependent growth, respectively. These inhibitory effects of FK866 were accompanied by significantly decreased expression of VEGF, MMP2, MMP9 and NF-κB. As determined by MTT assay and flow cytometry, FK866 also increased the chemosensitivity of gastric cancer cells to fluorouracil by greater inhibition of cell proliferation and the induction of apoptosis. Our findings indicate that Nampt may be a new therapeutic target for gastric cancer. IntroductionGastric cancer is the fourth most common malignancy in the world and causes ~800,000 deaths annually worldwide (1). For patients with recurrent, metastatic, or advanced gastric cancer, fluorouracil (5-FU) is a commonly used chemotherapeutic drug (2). However, the toxic side effects associated with 5-FU remain a significant challenge to its use. The development of more effective therapeutic drugs with minimal side effects is crucial, and is dependent on a better understanding of the molecular mechanism underlying gastric carcinogenesis.Nicotinamide adenine dinucleotide (NAD) is an essential cofactor found in all cells and plays key roles as a carrier of electrons during redox reactions. The rate-limiting enzyme involved in the biosynthesis of NAD from the nicotinamide precursor is nicotinamide phosphoribosyltransferase (Nampt) (3). Increasing evidence demonstrates that Nampt is a multifunctional enzyme and is important in metabolism and immune response as well as cancer (4). Nampt is also known as pre-B-cell colony enhancing factor (PBEF1), a presumptive cytokine (5), and as visfatin, an insulin-mimetic adipocytokine secreted by visceral fat (6) that is also encoded by the PBEF1 gene (5).Cross-talk between the two NAD-dependent enzymes SIRT1 (also known as sirtuin 1 or NAD-dependent deacetylase sirtuins-1) deacetylase and poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in cell viability under stress (7). By binding to and thereby causing the deacetylation of PARP1, SIRT1 protects cells from PARP1-mediated cell death. SIRT1 has also been shown to control PARP1 at the transcriptional level by negatively regulating the PARP1 gene promoter. The activity of SIRT1 can be positively regulated by Nampt, making Nampt a player in promoting cell survival under stress (8).Nampt was first reported to be overexpressed in colorectal cancer (9,10). It is also overexpressed i...

The cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology, contact inhibition and signal transduction during tumorigenesis. Protocadherin 8 (PCDH8), a member of the cadherin family, has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer. In this study, we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer. The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues. Methylation of the PCDH8 gene promoter was observed in 100% (4/4) of cell lines and 55.38% (36/65) of the primary gastric cancer by methylation-specific PCR, but not in normal gastric mucosa (0/10). Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis. The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines. Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis. For the first time, our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer. Thus, PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer.