DAPK and CIP2A are involved in GAS6/AXL-mediated Schwann cell proliferation in a rat model of bilateral cavernous nerve injury.

Yen-Lin Chen,Ying-Hung Lin,Shang-Shing P Chou,Yi-Ting Tsai,Chun-Hou Liao,Han-Sun Chiang,Meng-Chuan Chen,Yi-No Wu,Ting-Ting Chao

doi:10.18632/oncotarget.23978

Yen-Lin Chen, Ying-Hung Lin + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.23978

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Abstract

PurposeImpotence is one of the major complications occurring in prostate cancer patients after radical prostectomy (RP). Self-repair of the injured nerve has been observed in animal models and in patients after RP. However, the downstream signalling is not well documented. Here, we found that the DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation.Materials and MethodsThe 3 groups were a sham group, a 14-day post-bilateral cavernous nerve injury (BCNI) group and a 28-day post-BCNI group. Erectile function was assessed and immunohistochemistry was performed. The rat Schwann cell RSC96 line was chosen for gene knockdown, cell viability, western blot, immunofluorescence and co-immunoprecipitation assays.ResultsThe intracavernosal pressure was low on the 14th day after BCNI and partially increased by the 28th day. GAS6 and p-AXL expression gradually increased in the cavernous nerve after BCNI. RSC96 cells incubated with a GAS6 ligand showed increased levels of p-ERK1/2 and p-AKT. Moreover, DAPK and CIP2A.p-AXL and p-DAPK and CIP2A complexes were identified by both immunoblotting and co-immunoprecipitation.ConclusionThe DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation. CIP2A inhibits PP2A activity, which results in p-DAPK(S308) maintenance and promotes Schwann cell proliferation. CIP2A is a potential target for the treatment of nerve injury after RP.

Highlights

The incidence of prostate cancer has consistently increased and is still increasing globally [1, 2]
We found that the Death-associated protein kinase (DAPK)/cancerous inhibitor of protein phosphatase 2A (CIP2A) complex is involved in Growth arrest-specific protein 6 (GAS6)/AXL-related Schwann cell proliferation
The DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation

Summary

Introduction

The incidence of prostate cancer has consistently increased and is still increasing globally [1, 2]. Radical prostatectomy surgery is the gold standard treatment for localized prostate cancer; erectile dysfunction is a major complication of the procedure [3,4,5,6,7,8]. The regeneration of Schwann cell myelin sheaths was especially prominent on the 28th day after BCNI; more Ki-67-positive Schwann cells were present. This finding was consistent with the transmission electron microscope findings that revealed the presence of regeneration on the 28th day. In the peripheral nervous system, Schwann cells promote nerve regeneration by secreting trophic support molecules and establishing a supportive growth matrix. The identification of growth factors that promote Schwann cell outgrowth after nerve injury is an important strategy for improving nerve regeneration [9]

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