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Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression
Shibao Li1,2, Zhiyuan Wu2, Ping Ma1
1Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Abstract:
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.
Insights
Receptor tyrosine kinase EphA7 phosphorylation suppresses prostate cancer progression by inhibiting the PI3K/Akt pathway. EphA7 downregulation in tumors suggests its therapeutic potential for epithelial cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Receptor tyrosine kinase EphA7 downregulation is common in epithelial cancers, correlating with tumor progression.
- The precise mechanisms of EphA7 in prostate cancer (PCa) progression are not fully understood.
Purpose of the Study:
- To investigate the direct role of EphA7 receptor signaling in prostate cancer progression.
- To elucidate the molecular mechanisms underlying EphA7's function in PCa.
Main Methods:
- Generated EphA7 receptor variants (cytoplasmic domain deletion, phosphorylation-deficient mutant).
- Overexpressed wild-type (WT) EphA7 and mutants in PCa cells for in vitro and in vivo studies.
- Analyzed tumor volume, apoptosis, proliferation, migration, invasion, and downstream signaling pathways (Bax, Bcl-2, caspase-3, Akt).
- Assessed EphA7 and ephrinA5 expression in PCa tissues versus benign prostatic hyperplasia (BPH) and normal tissues.
Main Results:
- WT EphA7 overexpression reduced tumor volume, increased apoptosis, and inhibited PCa cell proliferation, migration, and invasion.
- EphA7-induced apoptosis involved increased Bax, elevated caspase-3 activity, decreased Bcl-2, and Akt dephosphorylation.
- EphA7 mutants lacking functional cytoplasmic domains showed no significant effects.
- EphA7 and ephrinA5 expression were significantly decreased in PCa tissues.
- EphA7 phosphorylation positively correlated with ephrinA5 expression in human prostate tissues.
Conclusions:
- Receptor phosphorylation of EphA7 suppresses prostate cancer malignancy.
- EphA7 signaling, particularly through Akt pathway dephosphorylation, plays a crucial role in inhibiting PCa progression.
- Restoring EphA7 function or expression may offer a therapeutic strategy for prostate cancer.