Sialidase NEU1 suppresses progression of human bladder cancer cells by inhibiting fibronectin-integrin α5β1 interaction and Akt signaling pathway

Abstract

Background: Sialic acids are widely distributed in animal tissues, and aberrantly expressed in a variety of cancer types. High expression of sialic acid contributes to tumor aggressiveness by promoting cell proliferation, migration, angiogenesis, and metastasis. Sialidases are responsible for removal of sialic acids from glycoproteins and glycolipids. Methods: N-glycomics of bladder cancer cells were detected by MALDI-TOF mass spectrometry. Sialic acid modification in bladder cancer tissue was determined by lectin blot. The down-regulation of NEU1 in bladder cancer cells was determined by high resolution liquid chromatography mass spectrometry (HR LC-MS). The effects of sialidase NEU1 expression on proliferation and apoptosis of human bladder cancer cells were examined by western blot, RT-PCR, confocal imaging and flow cytometry. Moreover, the function of sialic acids on fibronectinintegrin α5β1 interaction were assayed by immunoprecipitation and ELISA. The importance of NEU1 in tumor formation in vivo was performed using BALB/c-nu mice. Expression of NEU1 in primary human bladder cancer tissue samples was estimated using bladder cancer tissue microarray. Results: (1) Downregulation of NEU1 was primarily responsible for aberrant expression of sialic acids in bladder cancer cells. (2) Decreased NEU1 expression was correlated with bladder cancer progression. (3) NEU1 overexpression enhanced apoptosis and reduced proliferation of bladder cancer cells. (4) NEU1 disrupted FNintegrin α5β1 interaction and deactivated the Akt signaling pathway. (5) NEU1 significantly suppressed in vivo tumor formation in BALB/c-nu mice. Conclusions: Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. Our observations indicate that NEU1 is an important modulator of the malignant properties of bladder cancer cells, and is a potential therapeutic target for prognosis and treatment of bladder cancer.

Inhibitors of Human Neuraminidase Enzymes Block Transmigration in vitro

“…Sialic acids have been found to mediate a large number of glycoprotein interactions, including adhesion receptors such as the β1-integrin, a receptor for FN (Johansson et al, 1997;Schultz et al, 2012;Xie et al, 2021). In cancers that overexpress NEU1 the enzyme has been found to act as a negative regulator of migration through disruption of β1-and β4-integrin interactions (Uemura et al, 2009;Zhou et al, 2020).…”

The sialidase NEU1 directly interacts with the juxtamembranous segment of the cytoplasmic domain of mucin-1 to inhibit downstream PI3K-Akt signaling

“…Finally, Zhou et al. ( 69 ) recently reported that NEU1 overexpression in human bladder cancer cells diminished cell proliferation and enhanced apoptosis, in part, through disruption of PI3K-Akt signaling.

Figure 7 NEU1 disrupts the MUC1-CD/PI3K/Akt pathway: A proposed model.

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Glycocalyx sialic acids regulate Nrf2-mediated signaling by fluid shear stress in human endothelial cells

“…The endogenous sialidase NEU1 resides in two subcellular compartments with distinct homeostatic functions; lysosomal NEU1 regulates cytosolic SIA levels by recycling sialoconjugates [ 75 ], whereas in the plasma membrane it initiates inflammatory cascades via desialylation of surface molecules such as ICAM-1 [ 76 ] and TLR4 [ 77 ]. NEU1-mediated SIA cleavage also inhibits Akt signaling downstream of integrin α5β1 [ 78 ] and the latter mediates proinflammatory NF-kB activation in response to OSS [ 79 ]. In the present study, NEU1 silencing enhanced SIA expression in cells exposed to USS but had little effect on SIA levels following exposure to OSS, likely due to the sustained deficit in SIA biosynthesis described above.…”