10135

NAMPT

Boosting NAD(+) biosynthesis with NAD(+) intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD(+) biosynthesis, is frequently up-regulated in human malignancies, including breast cancer, suggesting possible protumorigenic effects for this protein. We addressed this issue by studying NAMPT expression and function in human breast cancer in vivo and in vitro. Our data indicate that high NAMPT levels are associated with aggressive pathological and molecular features, such as estrogen receptor negativity as well as HER2-enriched and basal-like PAM50 phenotypes. Consistent with these findings, we found that NAMPT overexpression in mammary epithelial cells induced epithelial-to-mesenchymal transition, a morphological and functional switch that confers cancer cells an increased metastatic potential. However, importantly, NAMPT-induced epithelial-to-mesenchymal transition was found to be independent of NAMPT enzymatic activity and of the NAMPT product nicotinamide mononucleotide. Instead, it was mediated by secreted NAMPT through its ability to activate the TGFbeta signaling pathway via increased TGFbeta1 production. These findings have implications for the design of therapeutic strategies exploiting NAD(+) biosynthesis via NAMPT in aging and cancer and also suggest the potential of anticancer agents designed to specifically neutralize extracellular NAMPT. Notably, because high levels of circulating NAMPT are found in obese and diabetic patients, our data could also explain the increased predisposition to cancer of these subjects.CI - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Visfatin is considered to be a biomarker in various types of cancers. However, no evidence has been reported for the direct effect of visfatin on osteosarcoma cell metastasis. The aims of the present study were to investigate the influence of visfatin on the migration and invasion of osteosarcoma cells and clarify the underlying mechanism. The expression levels of epithelial-mesenchymal transition (EMT) markers, as well as the transcriptional factor Snail-1, were first detected at both the protein and mRNA levels in U2OS osteosarcoma cells after stimulation of visfatin. Then the expression of NF-kappaB (p65) was detected by western blot analysis, and siRNA of Snail-1 and inhibitor of NF-kappaB were used to investigate the effect of visfatin. Finally, migration and invasion of the cells were detected respectively by scratch wound healing and transwell assays. Visfatin downregulated E-cadherin and upregulated N-cadherin in concentration- and time-dependent manners at the protein and mRNA levels. The expression of Snail-1 was also upregulated. Moreover, visfatin also promoted the nuclear translocation of the NF-kappaB pathway. Administration of siRNA of Snail-1 and the inhibitor BAY11-7082 validated the roles of Snail-1 and NF-kappaB in the visfatin-induced regulation of EMT markers. Migration and invasion of U2OS osteosarcoma cells were promoted following the application of visfatin. These results demonstrated that visfatin enhances the migration and invasion of osteosarcoma cells via the NF-kappaB/Snail-1/EMT pathway.

Increasing evidences suggested visfatin, a newly discovered obesity-induced adipocytokine, is involved in promotion of cancer malignancy and correlated with worse clinical prognosis. While its effects and mechanisms on progression of colorectal cancer (CRC) remain unclear. Our clinical data show that visfatin protein is over expressed, positive associated with lymph node metastasis, high-grade tumor, and poor prognosis in 87 CRC patients. The levels of plasma visfatin are significantly upregulated in Stage IV colon cancer. Visfatin can significantly promote the in vitro migration and invasion of CRC cells via induction epithelial mesenchymal transition (EMT). It can increase the expression and nuclear translocation of Snail, a key transcription factor in regulating EMT. While silencing of Snail attenuates visfatin induced EMT. Further studies reveal visfatin can inhibit the association of Snail with GSK-3beta and subsequently suppress ubiquitylation of Snail. In addition, visfatin can increase the expression and nuclear translocation of beta-catenin, elevate its binding with Snail promoter, and then increase the transcription of Snail. While inhibitor of PI3K/Akt, LY294002, abolishes visfatin induced up regulation of Snail, Vimentin (Vim), beta-catenin, and phosphorylated GSK-3beta. In summary, our data suggest that increased expression of visfatin are associated with a more aggressive phenotype of CRC patients. It can trigger the EMT of CRC cells via Akt/GSK-3beta/beta-catenin signals.