Stauprimide suppresses proliferation and survival via inhibition of IRF4 expression and activation of JNK in multiple myeloma cells

Abstract

　Multiple myeloma (MM) is a malignancy that develops from the uncontrolled proliferation of plasma cells. Although recent advances in drug development have significantly improved the overall survival rate of patients with MM, it remains incurable due to its eventual relapse. Therefore, the development of new agents is critical. Stauprimide is a staurosporine analog that inhibits the nuclear localization of the transcription factor non-metastatic cells 2 (NME2) in embryonic stem cells, thereby suppressing c-Myc transcription. Although it has anti-tumor effects in various cancer cell lines, its effects on MM cells have not been elucidated. We found that stauprimide suppressed proliferation through cell cycle arrest at the G2/M phase and induced apoptosis through poly ADP-ribose polymerase (PARP) activation in KMS-28PE and RPMI 8226 cells. Stauprimide suppressed interferon regulatory factor 4 (IRF4), which was followed by a c-Myc expression in KMS-28PE cells. Furthermore, stauprimide inhibited protein kinase C α (PKCα) constitutive phosphorylation and induced c-Jun N-terminal kinase (JNK) activation and transient c-Jun expression in KMS-28PE cells. These results indicated that stauprimide suppresses proliferation and induces apoptosis by inhibiting IRF-4 expression and PKCα phosphorylation, and via JNK activation in myeloma cells. Stauprimide should be further evaluated as a novel agent for MM.