RRC ID 62740
著者 Chung S, Kijima K, Kudo A, Fujisawa Y, Harada Y, Taira A, Takamatsu N, Miyamoto T, Matsuo Y, Nakamura Y.
タイトル Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor.
ジャーナル Oncotarget
Abstract MELK is upregulated in various types of human cancer and is known to be associated with cancer progression, maintenance of stemness, and poor prognosis. OTS167, a MELK kinase inhibitor, shows potent growth-suppressive effect on human tumors in a xenograft model, but the detailed mode of action has not been fully elucidated. In this study, we demonstrate the molecular mechanism of action of MELK inhibitor OTS167 in a preclinical model. OTS167-treated cells caused morphological transformation, induced the differentiation markers, and reduced stem-cell marker expression. Furthermore, we identified DEPDC1, known as an oncogene, as an additional downstream molecule of the MELK signaling pathway. MELK enhanced DEPDC1 phosphorylation and its stability. The expression of MELK and downstream molecules was decreased in OTS167-treated xenograft tumor tissues, which revealed central necrosis and significant growth suppression. Our data should further shed light on the mechanism of action how OTS167 suppresses tumor growth through the inhibition of the MELK signaling pathway and suggest the possibility of biomarkers for the assessment of clinical efficacy.
巻・号 7(14)
ページ 18171-82
公開日 2016-4-5
DOI 10.18632/oncotarget.7685
PII 7685
PMID 26918358
PMC PMC4951280
MeSH A549 Cells Animals Antineoplastic Agents / pharmacology* Biomarkers, Tumor COS Cells Cell Line, Tumor Cell Proliferation / drug effects Chlorocebus aethiops GTPase-Activating Proteins / metabolism* Humans Mice Mice, Inbred NOD Mice, SCID Naphthyridines / pharmacology* Neoplasm Proteins / metabolism* Neoplasms / drug therapy* Neoplasms / pathology Phosphorylation Protein Kinase Inhibitors / pharmacology* Protein Serine-Threonine Kinases / antagonists & inhibitors* Signal Transduction / drug effects Xenograft Model Antitumor Assays
IF 5.168
リソース情報
ヒト・動物細胞 COS-7(RCB0539)