TOPK (T‐LAK cell‐originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer

摘要

T‐lymphokine‐activated killer cell‐originated protein kinase (TOPK) plays critical roles in cancer cell proliferation as well as maintenance of cancer stem cells (CSC). Small cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC cell lines and primary tumors. Similar to siRNA‐mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC cell lines (IC 50; 0.4–42.6 nM) and led to their apoptotic cell death. TOPK inhibition caused cell morphologic changes in SCLC cells, elongation of intercellular bridges caused by cytokinesis defects or neuronal protrusions induced by neuronal differentiation in a subset of CSC‐like SCLC cells. Treatment with style="fixed-case">OTS514 suppressed forkhead box protein M1 ( style="fixed-case">FOXM1) activity, which was involved in stemness of style="fixed-case">CSC. Furthermore, style="fixed-case">OTS514 treatment reduced style="fixed-case">CD90‐positive style="fixed-case">SCLC cells and showed higher cytotoxic effect against lung sphere‐derived style="fixed-case">CSC‐like style="fixed-case">SCLC cells. Collectively, our results suggest that targeting style="fixed-case">TOPK is a promising approach for style="fixed-case">SCLC therapy.