Investigational agent MLN9708/2238 targets tumor suppressor microRNA-33b in MM cells
Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel, en régulant l'apoptose, le micro-ARN 33b joue un rôle de suppresseur de tumeurs dans les myélomes multiples
MicroRNA (miRNAs) play a critical role in tumor pathogenesis either as oncogenes or tumor suppressor genes. However, the role of miRNA and their regulation in response to proteasome inhibitors in multiple myeloma (MM) is unclear. miRNA profiling in proteasome inhibitor MLN2238-treated MM.1S MM cells shows upregulation of miR-33b. Mechanistic study indicates that induction of miR-33b is predominantly via transcriptional regulation. Examination of miR33b in patient MM cells showed a constitutively low expression. Overexpression of miR-33b decreased MM cell viability, migration, colony formation, as well as increased apoptosis and sensitivity of MM cells to MLN2238 treatment. Additionally, overexpression of miR-33b or MLN2238 exposure negatively regulates oncogene PIM-1 and blocks PIM-1-wild-type, but not PIM-1-mutant luciferase activity. Moreover, PIM-1 overexpression led to significant abrogation of miR-33b or MLN2238-induced cell death. SGI-1776, a biochemical inhibitor of PIM-1 triggered apoptosis in MM. Finally, overexpression of miR-33b inhibits tumor growth and prolongs survival in both subcutaneous and disseminated human MM xenograft models. Together, our study suggests that miR-33b is a tumor suppressor, which plays a role during MLN2238-induced apoptotic signaling in MM cells, and these data provide the basis for novel therapeutic strategies targeting miR-33b in MM.