Thromboxane a₂ Exerts Promoting Effects on the Proliferation of Multiple Myeloma Cells By Reducing G2/M Phase Arrest through the Activation of p38/JNK MAP Kinase Pathway

Background: Multiple myeloma is a kind of frequent hematological malignancy and its effective cure is still deficiency. Whether TXA₂/TP affects the proliferation of MM through the MAPK signaling pathway are still uncovered.

Results: SQ29548 inhibits the proliferation of MM cells by arresting cells at the G2/M phase through attenuating cyclin B1/CDK1 expression and p38 MAPK/JNK activation, and inducing cell apoptosis.

Conclusion: SQ29548 has potential as a novel agent to target kinase cascades for MM therapy.

Significance: We have defined a novel physiological role for TXA₂/TP in MM cells.

Multiple myeloma (MM) is a plasma cells malignant proliferation disease, and a satisfactory cure is unavailable till now. Thromboxane A2 (TXA₂)/TXA₂ receptor (TP) has involved the modulations of some carcinomas progression, while their effects on the proliferation of MM cells remain unclear. In this study, we detected cyclooxygenase enzymes (COX) downstream prostaglandin (PG) profiles in human myeloma cell lines U266 and RPMI8226, analyzed the effect of COX-1/-2 inhibitors, SC-560 and NS-398 on the MM cells proliferation. The observations showed that COX-2 involved in the modulation of cell growth. Then, MM cells were incubated with 4 antagonists of DP2, EP2, EP4 and TP receptors which were chosen according to their high transcriptions, and only TP antagonist, SQ29548, suppressed MM cells proliferation. Moreover, SQ29548 promoted MM cells G2/M phase arrest accompanied by reducing cyclin B1 and CDK1 expression at mRNA and protein levels. We also found TP agonist, U46619, activated JNK and p38 MAPK by phosphorylation, and JNK inhibitor, SP60015, and p38 MAPK inhibitor, SB203580, depressed U46619-induced proliferation and protein expressions of cyclin B1 and CDK1. In addition, SQ29548 leaded to MM cells apoptotic rate increasing with improving caspase 3 activity. Taken together, our results suggest that TXA₂/TP promote the proliferation of MM cells by reducing cells at the G2/M phase through elevating cyclin B1/CDK1 expression and p38 MAPK/JNK activation, and reducing cell apoptosis. It has potential as a novel agent to target kinase cascades for MM therapy.