Open AccessTOPK (T‐ LAK cell‐originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer
Author(s) -
Park JaeHyun,
Inoue Hiroyuki,
Kato Taigo,
Zewde Makda,
Miyamoto Takashi,
Matsuo Yo,
Salgia Ravi,
Nakamura Yusuke
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13160
Subject(s) - cancer research , cytokinesis , cytotoxic t cell , cell growth , protein kinase a , downregulation and upregulation , cell , lymphokine activated killer cell , cell culture , apoptosis , cancer stem cell , biology , kinase , stem cell , microbiology and biotechnology , cell division , in vitro , interleukin 21 , biochemistry , genetics , gene
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 si RNA ‐mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS 514, 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 OTS 514 suppressed forkhead box protein M1 ( FOXM 1) activity, which was involved in stemness of CSC . Furthermore, OTS 514 treatment reduced CD 90‐positive SCLC cells and showed higher cytotoxic effect against lung sphere‐derived CSC ‐like SCLC cells. Collectively, our results suggest that targeting TOPK is a promising approach for SCLC therapy.