Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression

Shibao Li,Zhiyuan Wu,Yinhai Xu,Yuming Chen,Hua Wang,Lingyu Yin,Ping Ma,Ping He,Ming Guan,Xiao Xu,Xinju Zhang,Yao Zhao,Zhihua Kang,Xiaochao Ma

doi:10.1038/cddis.2017.507

Shibao Li, Zhiyuan Wu + Show 12 more

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https://doi.org/10.1038/cddis.2017.507

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The downregulation of receptor tyrosine kinase EphA7 is frequent in epithelial cancers and linked to tumor progression. However, the detailed mechanism of EphA7-mediated prostate tumor progression remains elusive. To test the role of EphA7 receptor in prostate cancer (PCa) progression directly, we generated EphA7 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its phosphorylation by site-directed mutagenesis. Overexpression of wild-type (WT) EphA7 in PCa cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, ectopic expression of WT EphA7 both can delay PCa cell proliferation and could inhibit PCa cell migration and invasion. This protein can also induce PCa cell apoptosis that correlated with increasing the protein expression levels of Bax, elevating the caspase-3 activities, reducing the protein expression levels of Bcl-2 and facilitating the dephosphorylation of Akt, which is further increased by the stimulation of ephrinA5-Fc. However, expression of these EphA7 mutants in PCa cells has no effect in vivo and in vitro. The expression of EphA7 and ephrinA5 was significantly decreased in PCa specimens compared with BPH tissues or paired normal tissues. Moreover, the phosphorylation of EphA7 was positively related with ephrinA5 expression in human prostate tissues. In sum, receptor phosphorylation of EphA7, at least in part, suppress PCa tumor malignancy through targeting PI3K/Akt signaling pathways.

Highlights

Prostate cancer (PCa) is one of the most common male malignancy, and the second leading cause of death from cancer for men.[1]
Prior studies have shown that the optimum ligand of EphA7 is ephrinA5.15 We explored whether the optimum ligand of EphA7 is ephrinA5 in PCa, whether the phosphorylation of EphA7 receptors is related to the stimulation of endogenous ephrinA5 ligand in a cell–cell contact-dependent manner and whether the exogenous ephrinA5 ligand can further elevate the level of EphA7 tyrosine phosphorylation
The level of phosphorylated EphA7 receptor was upregulated by cell density, and was able to be further enhanced by the stimulation of exogenous ephrinA5 ligand (Figure 1c)

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Introduction

Prostate cancer (PCa) is one of the most common male malignancy, and the second leading cause of death from cancer for men.[1]. These results showed that the tyrosine phosphorylation of the EphA7 receptor was regulated by its ligand ephrinA5 and cell density.

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