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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

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Submitted:

03 February 2025

Posted:

04 February 2025

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Abstract
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.
Keywords: 
MST1/2 kinases inhibitor; hematopoietic tumors; programmed cell death; XMU-MP-1; cell cycle; cancer resistance; Hippo signaling pathways
Subject: 
Medicine and Pharmacology  -   Oncology and Oncogenics
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.

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