Koda Yuki, Itoh Mai, Tohda Shuji
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Anticancer Res. 2018 Jan;38(1):199-204. doi: 10.21873/anticanres.12208.
MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells.
Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated.
Treatment with the inhibitors suppressed cell growth and induced apoptosis in all cell lines. OCI/AML5 and TMD7 cells, in which MERTK was constitutively phosphorylated by autocrine mechanisms, were highly susceptible to these inhibitors. The treatment reduced the phosphorylation of MERTK and its down-stream signalling molecules, v-akt murine thymoma viral oncogene homolog 1 (AKT) and extracellular signal-regulated kinase (ERK). Similar effects were observed after MERTK knockdown. The inhibitors and the knockdown caused similar changes in mRNA expression.
These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK.
MER原癌基因酪氨酸激酶（MERTK）是一种影响癌细胞增殖的受体酪氨酸激酶。本研究评估了合成的MERTK抑制剂UNC569和UNC1062对急性髓系白血病（AML）细胞体外生长的影响。
用UNC569和UNC1062处理四种表达MERTK的AML细胞系，并分析细胞增殖、免疫印迹和基因表达情况。还评估了MERTK敲低的效果。
抑制剂处理抑制了所有细胞系的细胞生长并诱导凋亡。OCI/AML5和TMD7细胞中，MERTK通过自分泌机制持续磷酸化，对这些抑制剂高度敏感。处理降低了MERTK及其下游信号分子——v-akt小鼠胸腺瘤病毒癌基因同源物1（AKT）和细胞外信号调节激酶（ERK）的磷酸化。MERTK敲低后观察到类似效果。抑制剂和敲低导致mRNA表达发生类似变化。
这些MERTK抑制剂是治疗表达持续磷酸化MERTK的AML的潜在分子靶向药物。
