Purpose Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design We used human pancreatic cancer cells both in vitro (cell culture experiments) and in vivo (xenograft experiments) to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results We demonstrated that pharmacological and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1, nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo and further increases the sensitivity to Nampt inhibition. Conclusions Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer.
Tumor cell invasion is a highly integrated and complex process comprising several biologically distinct functions such as cell adhesion, motility, proteolysis, etc. Visininlike protein-1 (VILIP-1), a member of the neuronal EFhand calcium-sensor protein family, plays a role in regulating tumor cell invasiveness of mouse squamous cell carcinoma (SCC). VILIP-1 enhances cyclic adenosine monophosphate levels through PKA induction. However, the mechanism by which VILIP-1 reduces cell invasiveness is not well understood. In this study, we show that VILIP-1 decreased cell adhesion and migration/invasiveness of highly invasive mouse SCC cells. Forced expression of VILIP-1 reduced cell adhesion to fibronectin in parallel to downregulating av and a5 integrin subunit levels. VILIP-1 overexpression also led to decreased migration ability. Conversely, short hairpin RNA-mediated VILIP-1 knockdown of SCC cells' characterized by little or no invasiveness, correlated with increased adhesion to fibronectin and enhanced expression of av and a5 integrin subunits together with increased cell migration. Functionblocking assays with inhibitory anti-a5 and anti-av integrin antibodies showed that both subunits contributed to cell adhesion, migration, and invasiveness of highly invasive SCC cell lines. These results point to a critical role of VILIP-1 in regulating cell adhesion and migration by downregulation of fibronectin receptor expression. Decreased or absent VILIP-1 expression in SCC cell subpopulations may lead to a more advanced malignant phenotype characterized by changes in adhesive ability and increased cell motility, suggestive of a tumor suppressor function.
Purpose: Recent studies suggest that SIRT1-activating compounds (STAC) are a promising class of anticancer drugs, although their mechanism of action remains elusive. The main goal of this study is to determine the role of STACs as a potential therapy for pancreatic cancer. In addition, we also explored the mechanism by which these compounds affect pancreatic cancer.Experimental design: Using in vitro (cell culture experiments) and in vivo (xenograft experiments) approaches, we studied the role of SIRT1 agonists (STAC) in human pancreatic cancer cell viability and growth.Results: We show that SIRT1 is highly expressed in pancreatic cancer cells and that the STACs SRT1720, SRT1460, and SRT3025 inhibited cell growth and survival of pancreatic cancer cells. STACs enhanced the sensitivity of pancreatic cells to gemcitabine and paclitaxel, indicating that these drugs could be used in combination with other chemotherapy drugs. We also show that STACs were very effective in inhibiting tumor xenograft growth. In mechanistic studies, we observed that STACs activated a SIRT1 lysosomal-dependent cell death. Furthermore, the effect of STACs on cell viability was also dependent on the expression of the endogenous SIRT1 inhibitor DBC1.Conclusions: Taken together, our results reveal an essential role for SIRT1 and lysosomes in the death pathway regulated by STACs in pancreatic cancer cells. Clin Cancer Res; 22(10); 2496-507.Ó2015 AACR.
Introduction: Heterogeneity of nephrotic diseases and a lack of validated biomarkers limits interventions and reduces the ability to examine outcomes. Urinary CD80 is a potential biomarker for minimal change disease (MCD) steroid-sensitive nephrotic syndrome (NS). We investigated and validated a CD80 enzymelinked immunosorbent assay (ELISA) in urine in a large cohort with a variety of nephrotic diseases. Methods: A commercial CD80 ELISA was enhanced and analytically validated for urine. Patients were from Mayo Clinic (307) and Nephrotic Syndrome Study Network Consortium (NEPTUNE; 104) as follows: minimal change disease (MCD, 56), focal segmental glomerulosclerosis (FSGS, 92), lupus nephritis (LN, 25), IgA nephropathy (IgAN, 20), membranous nephropathy (MN, 49), autosomal dominant polycystic kidney disease (ADPKD, 10), diabetic nephropathy (DN; 106), pyuria (19), and controls (34). Analysis was by KruskalÀWallis test, generalized estimating equation (GEE) models, and receiver operating characteristic (AUC) curve.Results: Urinary CD80/creatinine values were highest in MCD compared to other glomerular diseases and were increased in DN with proteinuria >2 compared to controls (control ¼ 36 ng/g; MCD ¼ 139 ng/g, P < 0.01; LN ¼ 90 ng/g,
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