Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells.
Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells.
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发表时间：
2013-03
影响因子：
2
通讯作者：
Aya Ono;Ryo Oike;Yuki Okuhashi;Yusuke Takahashi;M. Itoh;N. Nara;S. Tohda
中科院分区：
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作者：
Aya Ono;Ryo Oike;Yuki Okuhashi;Yusuke Takahashi;M. Itoh;N. Nara;S. Tohda
目的PP 242是一种同时抑制哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）和mTORC 2的化合物。我们研究了PP 242和雷帕霉素对mTOR信号传导的影响，并在8个白血病细胞系中评估了与NOTCH信号传导的潜在串扰。材料和方法我们检测了用这些抑制剂处理对细胞生长和蛋白质表达的影响。结果PP 242比雷帕霉素更有效地抑制生长。在对PP 242敏感性差的两个细胞系中，PP 242未能抑制v-akt小鼠胸腺瘤病毒癌基因同源物（AKT）磷酸化。骨髓细胞系中mTOR磷酸化的抑制较弱。雷帕霉素诱导真核起始因子4 E结合蛋白1（4 E-BP 1）在三个细胞系中过度磷酸化。在三个细胞系中，S6激酶（S6 K）的两种亚型（p70和p85）的磷酸化被抑制;在其他细胞系中，只有p70被抑制。在一个细胞系中，PP 242上调NOTCH 1的表达和激活，但在另一个细胞系中下调。结论PP 242是白血病分子靶向治疗的候选药物，但其疗效必须根据具体情况进行评估。在mTOR和NOTCH信号通路之间发现了串扰。
AIM PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines. MATERIALS AND METHODS We examined the effects of treatment with these inhibitors on cell growth and protein expression. RESULTS PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another. CONCLUSION PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways.