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Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer

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 progn...

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Autores principales: Inoue, Hiroyuki, Kato, Taigo, Olugbile, Sope, Tamura, Kenji, Chung, Suyoun, Miyamoto, Takashi, Matsuo, Yo, Salgia, Ravi, Nakamura, Yusuke, Park, Jae-Hyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924666/
https://www.ncbi.nlm.nih.gov/pubmed/26871945
http://dx.doi.org/10.18632/oncotarget.7297
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author Inoue, Hiroyuki
Kato, Taigo
Olugbile, Sope
Tamura, Kenji
Chung, Suyoun
Miyamoto, Takashi
Matsuo, Yo
Salgia, Ravi
Nakamura, Yusuke
Park, Jae-Hyun
author_facet Inoue, Hiroyuki
Kato, Taigo
Olugbile, Sope
Tamura, Kenji
Chung, Suyoun
Miyamoto, Takashi
Matsuo, Yo
Salgia, Ravi
Nakamura, Yusuke
Park, Jae-Hyun
author_sort Inoue, Hiroyuki
collection PubMed
description 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 IC(50) 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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spelling pubmed-49246662016-07-13 Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer Inoue, Hiroyuki Kato, Taigo Olugbile, Sope Tamura, Kenji Chung, Suyoun Miyamoto, Takashi Matsuo, Yo Salgia, Ravi Nakamura, Yusuke Park, Jae-Hyun Oncotarget Research Paper 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 IC(50) 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. Impact Journals LLC 2016-02-10 /pmc/articles/PMC4924666/ /pubmed/26871945 http://dx.doi.org/10.18632/oncotarget.7297 Text en Copyright: © 2016 Inoue et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Inoue, Hiroyuki
Kato, Taigo
Olugbile, Sope
Tamura, Kenji
Chung, Suyoun
Miyamoto, Takashi
Matsuo, Yo
Salgia, Ravi
Nakamura, Yusuke
Park, Jae-Hyun
Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title_full Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title_fullStr Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title_full_unstemmed Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title_short Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer
title_sort effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (melk) inhibitor against small cell lung cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924666/
https://www.ncbi.nlm.nih.gov/pubmed/26871945
http://dx.doi.org/10.18632/oncotarget.7297
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