The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Background

Inhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear.

Design and Methods

Here, we evaluated whether nicotinamide phosphoribosyltransferase’s effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process.

Results

We identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation.

Conclusions

Our results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.     

烟酰胺磷酸核糖转移酶抑制剂的设计合成及抗肿瘤细胞增殖活性

目的寻找新的烟酰胺磷酸核糖转移酶（Nampt）抑制剂,为进一步药物设计提供依据。方法以进入临床研究的APO866为先导化合物,设计合成一系列Nampt抑制剂。以哌嗪为原料,经取代、SN2反应、Gabriel反应、成胍、环合等多步反应得到关键中间体（7a7,b）,该中间体再与酰氯衍生物反应,最终合成目标化合物。结果与结论合成了8个全新的Nampt抑制剂,化合物的结构经质谱和核磁共振氢谱确证;初步体外抗肿瘤实验结果表明,其中3个化合物（H1、H5、H7）具有一定的抗肿瘤活性,其活性与阳性对照APO866相当。     

High visfatin expression predicts poor prognosis of upper tract urothelial carcinoma patients

Visfatin, a newly discovered adipocytokine, is a pro-inflammatory cytokine. This study aimed to evaluate the predictive value of visfatin on prognosis of patients with upper tract urothelial carcinoma. One-hundred and five patients (median age=64, range=24-84 years) were included in this study. Visfatin expression in upper tract urothelial carcinoma tissues was analyzed by immunohistochemistry. Visfatin expression was correlated with clinicopathologic variables using the χ² test. The prognostic value of visfatin for recurrence-free and cancer-specific survival was evaluated by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Cox regression model was also used to evaluate the hazard ratios of visfatin on survival. High visfatin expression in upper tract urothelial carcinoma tissues was significantly correlated with tumor stage (P=0.001), grade (P=0.007) and p53 expression (P=0.07). High visfatin expression was associated with poor recurrence-free and cancer-specific survival. Cox regression analysis also revealed that visfatin is an independent predictor of recurrence-free (HR=3.22, P=0.009) and cancer-specific survival (HR=5.74, P=0.023). Our findings indicated that higher visfatin expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of visfatin in the carcinogenesis of upper tract urothelial carcinoma.     

烟酰胺磷酸核糖转移酶在子宫内膜癌中的表达及临床意义

目的:探讨烟酰胺磷酸核糖转移酶（Nampt）蛋白的表达与子宫内膜癌生物学行为之间的关系。方法:选取中国医科大学附属盛京医院2013年5月-2014年5月手术切除的40例子宫内膜癌组织（均为腺癌）及30例正常子宫内膜组织。采用实时定量逆转录聚合酶链反应（RT-PCR）检测其Nampt mRNA的表达、免疫组织化学SP法及蛋白免疫印迹检测Nampt蛋白的表达水平,并分析其表达量与子宫内膜癌临床病理学参数的关系。结果:Nampt mRNA在子宫内膜癌组织和正常子宫内膜组织中的相对表达量分别为3.774±2.399和1.286±0.762,差异有统计学意义（P＜0.05）。Nampt蛋白在子宫内膜癌组织和正常子宫内膜组织中的相对表达量分别为0.426±0.16和0.203±0.129,差异有统计学意义（P＜0.05）。在不同临床分期、不同肌层浸润的子宫内膜癌组织中Nampt蛋白的表达量有统计学差异（P＜0.05）。结论:Nampt蛋白的过度表达在子宫内膜癌的发生、发展过程中可能起到一定的作用。     

烟酰胺磷酸核糖转移酶的调控因素及药物作用

烟酰胺磷酸核糖转移酶（Nampt）是生命过程中不可或缺的蛋白,具有多种生理功能,对许多疾病如心脑血管疾病、糖尿病、癌症、自身免疫性疾病等有潜在的作用。阐明各种生理、病理状态以及化合物对Nampt表达水平的改变,可为Nampt的基础性和应用性研究起到推动作用。本文就各种因素对Nampt转录、表达调控的研究进展进行了较为系统的综述。     

An NAD+ biosynthetic pathway enzyme functions cell non‐autonomously in C. elegans development

Background: Disruption of cellular metabolite levels can adversely impact development. Specifically, loss‐of‐function of the C. elegans NAD⁺ salvage biosynthesis gene PNC‐1 results in an array of developmental phenotypes. Intriguingly, PNC‐1 and its functional equivalent in vertebrates are secreted, but the contributions of the extracellular enzymes are poorly understood. We sought to study the tissue‐specific requirements for PNC‐1 expression and to examine the role of the secreted isoform. Results: A thorough analysis of PNC‐1 expression did not detect expression in tissues that require PNC‐1 function. Limited expression of both the secreted and intracellular PNC‐1 isoforms provided function at a distance from the tissues with phenotypes. We also find that the secreted isoform contributes to in vivo PNC‐1 activity. Furthermore, uv1 cell survival has the most stringent requirements in terms of PNC‐1 expression pattern or level. Conclusions: Using careful promoter analysis and a restricted expression approach, we have shown that both the secreted and the intracellular PNC‐1 isoforms function cell non‐autonomously, and that the PNC‐1a isoform is functionally relevant in vivo. Our work suggests a model where PNC‐1 function is provided cell non‐autonomously by a mix of intra and extracellular activity, most likely requiring NAD⁺ salvage metabolite transport between tissues. Developmental Dynamics 243:965–976, 2014. © 2014 Wiley Periodicals, Inc.     

Nampt与糖尿病并发血管病变相关性的研究进展

尼克酰胺磷酸核糖转移酶（ Nampt）是生物合成烟酰胺腺嘌呤二核苷酸（ NAD）的关键限速酶, Nampt通过调节NAD的生成从而调控Sirt1的活性,参与细胞的分化、增殖及凋亡等过程。该文对Nampt与糖尿病并发血管病变相关性的研究进展作一综述。     

Nicotinamide phosphoribosyltransferase (Nampt) in carcinogenesis: new clinical opportunities

Introduction: Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes the first step in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Aberrant NAD metabolism was associated with oncogenic signal transduction, suggesting the critical roles of Nampt in tumorigenesis and metastasis. Additionally, Nampt can be secreted out of the cell, and this extracellular form of Nampt (eNampt) was shown to induce inflammation and angiogenesis due to its cytokine activity, which may also be involved in carcinogenesis.

Areas covered: This article reviews recent advances in the studies of Nampt in carcinogenesis, with a special highlight on Nampt inhibitors and future clinical application, including cancer diagnosis, prognosis and therapy.

Expert commentary: Nampt not only maintains the balance of cellular metabolism, but also has a profound influence on multiple aspects of carcinogenesis. Therefore, elucidation of these mechanisms opens the door for future clinical applications targeting this protein. Additional studies are needed to address important questions including the relationship between extracellular Nampt and carcinogenesis.