Abstract
Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC.
Highlights
Maternal embryonic leucine zipper kinase (MELK), known as MPK38, is involved in mammalian embryonic development and functions as a cell-cycle dependent protein kinase in the cell mitosis phase [1, 2]
To assess the MELK expression levels in small cell lung cancer (SCLC), we performed immunoblot analyses using 11 human SCLC cell lines and 2 normal fetal lung fibroblasts (NFLF) cell lines, and found that MELK protein was highly expressed in the majority of both adherent and suspension SCLC cell lines; whereas it was expressed in 2 NFLF normal counterparts at very low levels (Figure 1A and 1B)
methyl thiazolyl tetrazolium (MTT) assay revealed significant decrease of the cell viability in these SCLC cell lines transfected with siMELK, compared with those transfected with si-control (**p < 0.01 or ***p < 0.001) (Figure 2C)
Summary
MELK (maternal embryonic leucine zipper kinase), known as MPK38 (murine protein serine/ threonine kinase 38), is involved in mammalian embryonic development and functions as a cell-cycle dependent protein kinase in the cell mitosis phase [1, 2]. It is suggested that MELK is involved in the maintenance of cancer stem cells (CSCs), which possess higher tumorigenicity and are, in general, resistant to conventional anti-cancer therapies [6, 7]. Therapeutic strategies to target the MELK in CSCs should overcome the drawbacks of the conventional anti-cancer therapies. We reported development of a potent MELK inhibitor (OTS167) that effectively abrogated MELK kinase activity and suppressed growth of human breast cancer cells and acute myeloid leukemia cells [8, 9]. Our results demonstrated that OTS167 significantly inhibited the formation of mammosphere derived from breast cancer cells [9], implicating that OTS167 could be very effective to suppress the growth of CSCs
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