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

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

doi:10.18632/oncotarget.23978

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

Oncotarget. 2018 Jan 5;9(5):6402-6415. doi: 10.18632/oncotarget.23978. eCollection 2018 Jan 19.

Authors

Yen-Lin Chen^{1

2

3}, Yi-Ting Tsai¹, Ting-Ting Chao⁴, Yi-No Wu⁵, Meng-Chuan Chen⁶, Ying-Hung Lin³, Chun-Hou Liao^{3

7}, Shang-Shing P Chou², Han-Sun Chiang^{3

7}

Affiliations

¹ Department of Pathology, Cardinal Tien Hospital, New Taipei, Taiwan.
² Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan.
³ Graduate Institute of Biomedical and Pharmaceutical Science, Fu-Jen Catholic University, New Taipei, Taiwan.
⁴ Medical Research Center, Cardinal Tien Hospital, New Taipei, Taiwan.
⁵ School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.
⁶ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
⁷ Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, Taiwan.

Abstract

Purpose: Impotence 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 methods: The 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.

Results: The intracavernosal pressure was low on the 14^th day after BCNI and partially increased by the 28^th 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.

Conclusion: The 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.

Keywords: CIP2A; DAPK; GAS6/AXL; Schwann cell; cavernous nerve.