XMU-MP-1, Inhibitor of STE20-like MST1/2 Kinases of the Hippo Signaling Pathway, Suppresses the Cell Cycle, Activates Apoptosis and Autophagy, and Induces Death of Hematopoietic Tumor Cells
- Pharmaceuticals (Basel). 2025 Jun 12;18(6):874. doi: 10.3390/ph18060874.
- 1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, 119991 Moscow, Russia.
- 2. Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, 119991 Moscow, Russia.
Background/Objectives: Currently, there is limited knowledge on the molecular mechanisms of the "non-canonical" Hippo signaling pathway in hematopoietic tumor cells. We have shown that targeting the MST1/2 kinases, which are the key molecules in this signaling pathway, may be an effective approach to the treatment of hematologic tumors. Methods: The methods used in this study include cell growth assays, Caspase assays, Western blot hybridizations, flow cytometry, and whole-transcriptome analyses. These methods allowed us to better understand the molecular pathways at play. Results: Our results showed that XMU-MP-1, an inhibitor of MST1/2 kinase, specifically reduces the viability of hematopoietic Cancer cells but not breast Cancer cells. It effectively inhibits the growth of the tumor B- and T-cell lines by blocking cell cycle progression, mainly during the G2/M phase, inducing Apoptosis and Autophagy. XMU-MP-1 treatment led to increased Caspase 3/7 activity and increased levels of the cleaved PARP protein. Levels of the LC3-II protein were also shown to be increased, while the level of p62 decreased. These changes are associated with Apoptosis and Autophagy, respectively. RNA-seq analysis has demonstrated that XMU-MP-1 suppressed the expression of cell cycle regulators, such as E2F, and cell division cycle genes CDC6,7,20,25,45; cyclins A2,B1,B2, and cyclin-dependent kinases. At the same time, it increased the expression of genes involved in Apoptosis, Autophagy, and Necroptosis. Conclusions: Combinations of growth assays, Caspase assays, Western blotting, and RNA-seq have shown that the dramatic reduction in the number of hematopoietic tumor cells after treatment with XMU-MP-1 is due to both cytostatic and cytotoxic effects. The use of MST1/2 kinase inhibitors could be highly promising for complex therapy of hematological tumors.