Institute of Urology, Capital Medical University, Beijing, China.
Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China.
Biosci Rep. 2019 Jul 30;39(7). doi: 10.1042/BSR20182270. Print 2019 Jul 31.
Bladder cancer (BC) is one of the commonest malignancies in the urinary system. Recent evidences have shown that Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) serves as a tumor suppressor in hepatocellular carcinoma and cervical cancer. However, little is known about its function in BC. Here, we aimed to investigate the role of LHPP in BC. We found that LHPP was down-regulated in BC tissues and cells. Knockdown of LHPP promoted the proliferation and growth of BC cells T24 and 5637. Inverse results were observed in SW780 and BIU87 cells with ectopic LHPP expression. LHPP also repressed the glycolysis of BC cells. At the molecular level, LHPP silencing led to enhanced phosphorylation of both AKT and p65, as well as up-regulation of their downstream targets Bcl-2 and Cyclin D1. Inhibition of AKT by MK2206 blunted the increased phosphorylation of p65 caused by LHPP knockdown, suggesting that LHPP silencing activated p65 through AKT. Importantly, p65 inhibitor (caffeic acid phenethyl ester) exhibited larger suppressive effect on the proliferation of LHPP knockdown BC cells as compared with Ctrl cell. Our study demonstrates that LHPP suppresses BC cell growth via inactivating AKT/p65 signaling pathway.
膀胱癌（BC）是泌尿系统中最常见的恶性肿瘤之一。最近的证据表明，磷酸丝氨酸磷酸组氨酸无机焦磷酸酶（LHPP）在肝细胞癌和宫颈癌中作为肿瘤抑制因子发挥作用。然而，关于其在 BC 中的功能知之甚少。在这里，我们旨在研究 LHPP 在 BC 中的作用。我们发现 LHPP 在 BC 组织和细胞中下调。LHPP 的敲低促进了 BC 细胞 T24 和 5637 的增殖和生长。在异位 LHPP 表达的 SW780 和 BIU87 细胞中观察到相反的结果。LHPP 还抑制了 BC 细胞的糖酵解。在分子水平上，LHPP 沉默导致 AKT 和 p65 的磷酸化增强，以及它们的下游靶标 Bcl-2 和 Cyclin D1 的上调。通过 MK2206 抑制 AKT 减弱了 LHPP 敲低引起的 p65 磷酸化增加，表明 LHPP 沉默通过 AKT 激活了 p65。重要的是，与对照细胞相比，p65 抑制剂（咖啡酸苯乙酯）对 LHPP 敲低的 BC 细胞增殖的抑制作用更大。我们的研究表明，LHPP 通过失活 AKT/p65 信号通路抑制 BC 细胞生长。
