LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway.

Yansheng Li,Xiaodong Zhang,Xiaoguang Zhou,Xin Zhang

doi:10.1042/bsr20182270

Abstract

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.

Highlights

Bladder cancer (BC), which generally originates from the epithelium, represents the fourth most frequent malignancy in men and the ninth commonest cancer in women [1]
We firstly explored the clinical significance of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) in BC by checking the protein and mRNA abundance of LHPP
We showed that LHPP protein level was reduced in BC tissues as compared with normal tissues (Figure 1A)

Summary

Introduction

Bladder cancer (BC), which generally originates from the epithelium, represents the fourth most frequent malignancy in men and the ninth commonest cancer in women [1]. Dysregulation of kinases or phosphatases, such as PI3K, AKT, PTEN or DUSPs, is widely observed in cancers. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is conserved from worm to human with a 28% identity [5]. It is originally discovered in swine brain tissue [6,7]. LHPP has been identified as a tumor suppressor gene in hepatocellular carcinoma (HCC) by targeting PI3K/AKT signaling pathway. It is lowly expressed in HCC specimens and its low expression correlates with the poor survival of HCC patients [5]. The role of LHPP in other cancer types, such as BC, is largely unknown

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