Over-Expression of RPS3 Promotes Acute Lymphoblastic Leukemia Growth and Progress By Down-Regulating COX-2 through NF-κb Pathway

The Ribosome protein S3 (RPS3) is a component of 40S ribosomal subunit, which is important in ribosomal maturation.In addition, RPS3 plays a central role in the regulation of cell cycle,proliferation,migration,DNA repair,and apoptosis.Recent study has also been reported that RPS3 is secreted as a homodimer in cancer cells. The increased level of secreted RPS3 was detected in more malignant cells.These findings suggest that the RPS3 protein is an indicator of malignant tumors.Therefore, we studied the roles and the functions mechanisms of RPS3 in leukemia in order to understand whether RPS3could be a key target for leukemia therapy.

qRT-PCR and western blot analysis were carried out in a small cohort of acute lymphoblastic leukemia patients(ALL) and multiple leukemia cell lines to evaluate RPS3 mRNA and protein expression levels.To assess its biological functions relevance, its expression was down modulated by transient RNA interference in ALL cell lines.Our results show that RPS3 mRNA and protein expression is higher in both ALL patients and the ALL cell lines when compared to the healthy donors peripheral blood mononuclear cell or myeloid leukemia cell lines. Correspondence with this, the ALL patients with higher expression of RPS3 had shorter overall survival than those with lower expression of RPS3 (25.1% vs. 63.4%, P<0.001, for 5 year-OS).Furthermore,blocking RPS3 activity in four ALL cell lines, by either knockdown or treatment with the RPS3 inhibitor, causes significant decrease in their cell proliferation.This decrease in cell proliferation was coupled with both an induction of the G1/S cell cycle arrest and with an increase of apoptosis induced in the leukemia population. In vivo,we also found that knockdown of RPS3 significantly inhibited tumor growth in a ALL xenograft mouse model. Finally, mechanism studies showed that RPS3 knockdown in ALL cells triggered suppression of COX-2 expression and its down-stream targets PGE2 release,inhibited COX-2 promoter activity by decreased P50 /P65 Binding to cox2 promotor.

In conclusion,our results suggest that overexpression of RPS3 promotes acute lymphoblastic leukemia growth and progress by up-regulating COX-2 through NF-κB pathway. and that targeting RPS3could be an attractive strategy for ALL therapy.