Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Urology, Taipei Medical University Shuang-Ho Hospital, Zhong-He District, New Taipei City 23561, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei, 11031, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Biochim Biophys Acta Mol Basis Dis. 2024 Apr;1870(4):167106. doi: 10.1016/j.bbadis.2024.167106. Epub 2024 Feb 29.
Bladder cancer (BLCA) is one of the most prevalent malignancies worldwide with a high mortality rate and poor response to immunotherapy in patients expressing lower programmed death ligand 1 (PD-L1) levels. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme responsible for the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide was reported to be overexpressed in various cancers; however, the role of NAMPT in BLCA is obscure. Immunohistochemistry of tissue microarrays, a real-time polymerase chain reaction, Western blotting, proliferation assay, NAD quantification, transwell-migration assay, and colony-formation assay were performed to measure NAMPT and PD-L1 expression levels in patients and the effect of NAMPT inhibition on T24 cells. Our study revealed that NAMPT expression was upregulated in BLCA patients with different grades and associated with poor T-cell infiltration. Notably, FK866-mediated NAMPT inhibition decreased cell viability by depleting NAD, and reducing the migration ability and colony-formation ability of T24 cells. Interestingly, NAMPT negatively regulated PD-L1 under an interferon (IFN)-γ-mediated microenvironment. However, exogenous NAMPT activator has no effect on PD-L1. NAD supplementation also only increased PD-L1 in the absence of IFN-γ. Conclusively, NAMPT is crucial for BLCA tumorigenic properties, and it regulates expression of the PD-L1 immune checkpoint protein. NAMPT could be considered a target for modulating sensitivity to immunotherapy.
膀胱癌（BLCA）是全球最常见的恶性肿瘤之一，其死亡率较高，且对表达较低程序性死亡配体 1（PD-L1）水平的患者的免疫治疗反应不佳。烟酰胺磷酸核糖转移酶（NAMPT）是一种限速酶，负责从烟酰胺合成烟酰胺腺嘌呤二核苷酸（NAD），据报道在各种癌症中过度表达；然而，NAMPT 在 BLCA 中的作用尚不清楚。通过进行组织微阵列的免疫组织化学、实时聚合酶链反应、Western blot、增殖测定、NAD 定量、Transwell 迁移测定和集落形成测定，来测量患者中 NAMPT 和 PD-L1 的表达水平，以及 NAMPT 抑制对 T24 细胞的影响。我们的研究表明，NAMPT 在不同分级的 BLCA 患者中表达上调，并与 T 细胞浸润不良相关。值得注意的是，FK866 介导的 NAMPT 抑制通过消耗 NAD 降低细胞活力，并降低 T24 细胞的迁移能力和集落形成能力。有趣的是，NAMPT 在干扰素（IFN）-γ介导的微环境下负调控 PD-L1。然而，外源性 NAMPT 激活剂对 PD-L1 没有影响。NAD 补充剂也仅在没有 IFN-γ 的情况下增加 PD-L1。总之，NAMPT 对 BLCA 的肿瘤发生特性至关重要，并且它调节 PD-L1 免疫检查点蛋白的表达。NAMPT 可被视为调节免疫治疗敏感性的靶标。
