Engagement of CD47 induces G1 arrest in EBV-transformed B cells by controlling CDK-cyclin-CDKi and activating p38 MAPK/JNK pathway (P2149)

Abstract

Abstract CD47 possesses a variety of anti-tumor, anti-angiogenic, and anti-metastatic properties in several tumors, but its roles on EBV-transformed B cells are still not fully understood. Here we first observed that EBV infection induced CD47 expression on B cells surface, and CD47 stimulation of EBV-transformed B cells with anti-CD47 mAb (B6H12) reduced cell proliferation and induced the cell cycle arrest at G1-phase. We showed that CD47-induced G1-phase arrest was mediated through increased expression of CDKi (p16INK4a, p21WAF1, and p53), a simultaneous decreased expression in CDK2, 4, 6 and cyclin D1, D2 and E and enhanced binding of CDKi-CDK. Among the relevant pathways, CD47 mAb induced outstanding activation of p38 MAPK and JNK, whereas phosphorylation of Akt and ERK1/2 were both reduced. In particular, p38 inhibitor SB203580 and JNK inhibitor SP600125 powerfully blocked the decreased expression of CDK and the increased expression of CDKi and dramatically suppressed binding of phospho-p38-CDKi. Accordingly, these data demonstrate that the p38 MAPK and JNK pathway participates in CDKi induction, subsequently leading to a decrease in the levels of cyclin D1-CDK4/6 and cyclin E-CDK2 complexes and CD47-dependent EBV-transformed B cell growth inhibition. In conclusion, these findings concerning the molecular mechanisms of CD47 signaling in EBV-transformed B cells provides a theoretical basis for clinical approaches for the use of therapeutic agents in treating EBV-associated tumors.