Effective Growth-suppressive Activity of Maternal Embryonic Leucine-zipper Kinase (MELK) Inhibitor Against Small Cell Lung Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Feb 13

PMID 26871945

Citations 31

Authors

Hiroyuki Inoue

Taigo Kato

Sope Olugbile

Kenji Tamura

Suyoun Chung

Takashi Miyamoto

Yo Matsuo

Ravi Salgia

Yusuke Nakamura

Jae-Hyun Park

Affiliations

Soon will be listed here.

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.

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