Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation
Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation
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DOI：
10.1158/0008-5472.can-08-2608
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Khwaja, Asim
中科院分区：
文献类型：
--
作者：
Billottet, Clotilde;Banerjee, Lalita;Khwaja, Asim
我们研究了磷脂酰肌醇3-激酶（PI 3 Ks）在急性早幼粒细胞白血病（APL）体外病理生理学中的作用，以及对全反式维甲酸（ATRA）治疗的反应，利用一系列针对PI 3 K的单个或所有催化I类亚型（p110 α，p110 β，p110 δ和p110 γ）的新型抑制剂。APL细胞中ATRA诱导的Akt激酶和核糖体S6蛋白磷酸化对I类PI 3 K和p110 β或p110 δ抑制剂以及雷帕霉素哺乳动物靶蛋白（mTOR）抑制剂雷帕霉素敏感。在原发性APL中，在不存在或存在ATRA的情况下，p110 β或p110 δ的抑制都会引发细胞凋亡。I类PI 3 K抑制也可以逆转ATRA诱导的这些细胞对阿霉素和三氧化二砷的保护，与抗凋亡MCL-1蛋白的诱导受损相关。ATRA的诱导分化作用不依赖于I类PI 3 K/mTOR。总之，由p110 β和p110 δ介导的I类PI 3 K信号在APL的基础和ATRA诱导的细胞存活机制中起重要作用。在诱导治疗方案中添加PI 3 K抑制剂可提供治疗益处。[Cancer Res 2009;69（3）：1027-36]
We have investigated the role of phosphoinositide 3-kinases (PI3Ks) in the in vitro pathophysiology of acute promyelocytic leukemia (APL) and in the response to treatment with all-trans-retinoic-acid (ATRA), utilizing a range of novel inhibitors that target individual or all catalytic class I isoforms of PI3K (p110 alpha, p110 beta, p110 delta, and p110 gamma). ATRA-induced phosphorylation of the Akt kinase and ribosomal S6 protein in APL cells was sensitive to class I PI3K, and p110 beta or p110 delta inhibitors, and to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In primary APL, inhibition of p110 beta or p110 delta triggered apoptosis in the absence or presence of ATRA. Class I PI3K inhibition could also reverse ATRA-induced protection of these cells against doxorubicin and arsenic trioxide, correlating with impaired induction of the antiapoptotic MCL-1 protein. The differentiation-inducing effects of ATRA were not dependent on class I PI3K/mTOR. In summary, class I PI3K signaling, mediated by p110 beta and p110 delta, plays an important role in basal and ATRA-induced cell survival mechanisms in APL. Addition of PI3K inhibitors to induction treatment regimens may provide therapeutic benefit. [Cancer Res 2009;69(3):1027-36]