Threonine and tyrosine kinase promotes multiple myeloma progression by regulating regucalcin expression

Abstract

Multiple myeloma (MM) is a malignant proliferative disorder of plasma cells and remains an incurable disease. Threonine and tyrosine kinase (TTK) is a dual-specific protein kinase that targets serine/threonine and tyrosine residues for phosphorylation. Its elevated expression has been linked to unfavorable outcomes in several types of cancer. Although the role of TTK in MM are still incompletely understood. In this research, we assessed TTK mRNA and protein expression levels in 51 MM patients and 30 healthy donors using qRT-PCR and western blotting. The impact of TTK expression on MM cell apoptosis, proliferation, and the cell cycle were assessed through CCK-8 assay, flow cytometry, and western blotting. Our findings revealed a significant overexpression of TTK in multiple myeloma patients and cell lines. TTK knockdown promoted apoptosis and G0/G1 phase arrest while inhibiting proliferation in MM cells, whereas TTK overexpression reduced apoptosis and G0/G1 phase arrest, enhancing proliferation in MM cells. Next, we identified regucalcin (RGN) as a downstream target of TTK through proteomic analysis. In NDMM, the expression of RGN was decreased. Cell function experiments showed that RGN knockdown significantly promoted MM cell proliferation, inhibited apoptosis and reduced cell cycle arrest, and reversed the increased apoptosis, weakened proliferation, and enhanced cell cycle arrest caused by TTK knockdown. Finally, a xenograft mouse model showed that TTK significantly promotes MM development. In summary, we demonstrated that the TTK-RGN axis regulates cell apoptosis, G0/G1 phase arrest, and proliferation in MM, highlighting TTK as a potential target for therapeutic intervention in this cancer.