Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells
Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells
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DOI：
10.1182/blood-2005-03-0929
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发表时间：
2005-08-15
期刊：
影响因子：
20.3
通讯作者：
Romano, MF
中科院分区：
文献类型：
--
作者：
Avellino, R;Romano, S;Romano, MF
磷脂酰肌醇 3 激酶 (Pl3k)/Akt 通路与儿童急性淋巴细胞白血病 (ALL) 有关。由于雷帕霉素抑制 PI3k/Akt 维持的致癌过程，因此我们研究了雷帕霉素是否影响胚细胞存活。我们发现雷帕霉素在所分析的骨髓样本中 56% 会诱导母细胞凋亡。使用 PI3k 抑制剂渥曼青霉素，我们证明 PI3k/Akt 途径参与胚芽存活。此外，即使在无反应样本中，雷帕霉素也会增加阿霉素诱导的细胞凋亡。蒽环类药物可激活核因子 kappa B (NF-kappa B)，破坏该信号通路可提高凋亡刺激的功效。雷帕霉素可抑制所有样本中阿霉素诱导的 NF-κ B。使用短干扰 (si) RNA 方法，我们证明 FKBP51（一种受雷帕霉素抑制的大亲免素）对于人类白血病中药物诱导的 NF-κ B 激活至关重要。此外，当 NF-κ B 过表达时，雷帕霉素不会增加阿霉素诱导的细胞凋亡。总之，雷帕霉素靶向对恶性淋巴细胞的细胞存活和化疗耐药至关重要的 2 条途径 - 通过雷帕霉素的哺乳动物靶标 Pl3k/Akt 和通过 FKBP51 的 NF-kappa B - 表明该药物可能有益于治疗儿童 ALL。
The phosphatidyl-inositol 3 kinase (Pl3k)/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in nonresponder samples. Anthracyclines activate nuclear factor kappa B (NF-kappa B), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-kappa B in ALL samples. Using a short interfering (si) RNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-kappa B activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-kappa B was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts-Pl3k/Akt through the mammalian target of rapamycin and NF-kappa B through FKBP51-suggesting that the drug could be beneficial in the treatment of childhood ALL.