XMU-MP-1, Inhibitor of STE20-like MST1/2 Kinases of the Hippo Signaling Pathway, Induces Hematopoietic Tumor Cells Death by Suppressing the Cell Cycle and Activating Apoptosis, Necroptosis and Autophagy

Currently there is little knowledge on the molecular mechanisms of the “non-canonical” Hippo signaling pathway in hematopoietic tumor cells. We have showed that targeting the MST1/2 kinases, the key molecules in the Hippo signaling pathway may prove to be an effective way to treat hematologic tumors. In the present study, we have shown that inhibitor MST1/2 kinases - XMU-MP-1 effectively inhibits the growth of tumor B- and T-cells. XMU-MP-1 blocking the cell cycle and inducing cell death by apoptosis, necroptosis, and autophagy. XMU-MP-1 enhances doxorubicin effects. RNA-Seq analysis has demonstrated that XMU-MP-1 suppresses the expression of the key cell cycle regulators in the Namalwa cells: E2F, cell division cycle genes (CDC6,7; CDC20; CDC25A,В,С, CDC45), cyclins CCNА2, CCNB1,B2; MCM2-7, ORC1, ORC6. At the same time, 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, PEA15. The expression of the key genes activating autophagy is significantly increased (beclin1; DEPP1; DAP; VPS18; VPS39, autophagy regulator AMBRA1). The use of MST1/2 kinase inhibitors in the treatment of hematologic tumors may be extremely promising.