Alterations of serine racemase expression determine proliferation and differentiation of neuroblastoma cells

Abstract Genetic deletion of serine racemase(SR) causes development disability of neuronal dendrites whereas increased expression of SR is found in differentiated cells in culture. These observations suggest roles of SR in cell proliferation and differentiation. Very recently,we have characterized increased SR expression when a neuroblastoma cell line,N2A,undergoes differentiation. However,whether and how the expression levels of SR determine cell destiny remains unclear. We herein indicated that valproic acid(VPA) or all-trans retinoic acid induced N2A differentiation which was mitigated by knockdown of SR. Knockdown of SR increased N2A proliferation,promoted cell cycle entry,and modulated expression of cell cycle-related proteins in N2A cells. Tumor formation in nude mice was used to further examine the effect of SR expression on cell destiny. N2A cells stably expressing scramble shRNA(Srrwt-N2A) or Srr shRNA (Srrkd-N2A) were subcutaneously injected into nude mice,respectively. The tumors growing from Srrwt-N2A,significantly mitigated by intraperitoneal injection of VPA,were smaller than the tumors growing from Srrkd-N2A which were not affected by VPA. With R2 program,the levels of SR expression were predicted to be positively correlated with survival probability in neuroblastoma patients. This study unveils that alteration of SR modulated proliferation and differentiation of neuroblastoma cells and the mechanism. The results further suggest that induction of SR expression is a novel strategy to treat neuroblastoma.