XMU-MP-1, an inhibitor of the STE20-like MST1/2 kinases of the Hippo signaling pathway, induces hematopoietic tumor cells death

In this study we have shown that treatment of hematopoietic cells with XMU-MP-1, the inhibitor of MST1/2, the key components of the Hippo signaling pathway, causes inhibition of cell population growth and increased levels of caspase 3/7 activity. RNA-Seq analysis has demonstrated that XMU-MP-1 suppresses the expression of the key cell cycle regulators in the Namalwa cells: E2F family transcription factors, cell division cycle genes (CDC6; CDC7; CDC20; CDC25A,В,С, and CDC45), cyclins CCNА2, CCNB1, CCNB2; MCM2-7, ORC1 and ORC6. At the same time, XMU-MP-1 triggers the activation of the genes regulating apoptosis, necroptosis, and autophagy. XMU-MP-1 increases the expression of the apoptosis activator genes APAF1, caspases 6 and 7, FAS; BBC3, BCL2A1, MOAP1; XAF1. Some Namalwa cells may undergo necroptosis: XMU-MP-1 causes an increase in the expression of the necroptosis activator genes RIPK1, TNFSF10, TRADD, and PEA15, the inhibitor of caspase 8. The expression of the key genes activating autophagy is significantly increased (beclin 1; DEPP1; DAP; VPS18; VPS39, and autophagy regulator AMBRA1). The activation of these three processes in the B-cell tumor population indicates a profound effect of XMU-MP-1 on cell death in hematopoietic tumor cells. The treatment of Namalwa cells with XMU-MP-1 decreases their resistance to doxorubicin. The use of MST1/2 kinase inhibitors in the treatment of hematologic tumors may be extremely promising.