Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells
Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells
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DOI：
10.1016/j.leukres.2006.08.001
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发表时间：
2007-05-01
影响因子：
2.7
通讯作者：
Taguchi, Hirokuni
中科院分区：
文献类型：
--
作者：
Ikezoe, Takayuki;Nishioka, Chie;Taguchi, Hirokuni
本研究发现，磷脂酰肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号在人类嗜T淋巴细胞病毒I型（HTLV-1）感染的白血病细胞中被激活。雷帕霉素（1-100 nM，48 h），mTOR及其类似物RAD 001的抑制剂（1-100 nM，48 h）诱导的这些细胞的生长抑制和G 0/G1细胞周期阻滞与p70 S6 K和4 E-BP-1的去磷酸化有关，尽管未达到IC 50。特别地，雷帕霉素刺激Akt在Ser 473的磷酸化。PI 3 K抑制剂LY 294002（1-20 μ M，48 h）阻断Akt信号传导也导致HTLV-1感染细胞的生长抑制和G 0/G1细胞周期停滞，IC 50范围为5 - 20 μ M，并导致p70 S6 K和4 E-BP-1去磷酸化。值得注意的是，当雷帕霉素与LY 294002组合时，雷帕霉素诱导的Akt磷酸化被阻断，并且雷帕霉素诱导HTLV-1感染的T细胞的生长停滞和抑制p-p70 S6 K和p-4 E-BP-1蛋白的能力增强。此外，LY 294002和雷帕霉素都下调了这些细胞中c-Myc和cyclin D1蛋白的水平，并且它们的组合进一步降低了这些细胞周期调节蛋白的水平。总之，PI 3 K/Akt/mTOR信号传导的纵向抑制代表了患有成人T细胞白血病的个体的有希望的治疗策略。(c)2006爱思唯尔有限公司保留所有权利。
This study found that phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling was activated in human T-cell lymphotropic virus type I (HTLV-1)-infected leukemia cells. Rapamycin (1-100 nM, 48h), the inhibitor of mTOR and its analog RAD001 (1-100 nM, 48 h)-induced growth inhibition and G0/G1 cell cycle arrest of these cells in association with de-phosphorylation of p70S6K and 4E-BP-1, although IC50 was not achieved. Paradoxically, rapamycin-stimulated phosphorylation of Akt at Ser473. Blockade of Akt signaling by the PI3K inhibitor LY294002(1-20 mu M, 48 h) also resulted in the growth inhibition and G0/G1 cell cycle arrest of HTLV-1-infected cells, with IC50 ranging from 5 to 20 mu M, and it caused de-phosphorylation of p70S6K and 4E-BP-1. Of note, when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Moreover, both LY294002 and rapamycin down-regulated the levels of c-Myc and cyclin D1 proteins in these cells, and their combination further decreased levels of these cell cycle-regulating proteins. Taken together, longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with adult T-cell leukemia. (c) 2006 Elsevier Ltd. All rights reserved.