Sorafenib Inhibition of Mcl-1 Accelerates ATRA-Induced Apoptosis in Differentiation-Responsive AML Cells.
Sorafenib Inhibition of Mcl-1 Accelerates ATRA-Induced Apoptosis in Differentiation-Responsive AML Cells.
复制标题
DOI：
10.1158/1078-0432.ccr-15-0663
复制
发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Jing Y
中科院分区：
文献类型：
--
作者：
Wang R;Xia L;Gabrilove J;Waxman S;Jing Y
全反式维甲酸（ATRA）通过诱导终末分化介导的细胞死亡成功治疗急性早幼粒细胞白血病（APL），但对非APL急性髓细胞白血病（AML）的活性有限。我们的目的是通过抑制抗凋亡蛋白Bcl-2和Mcl-1来增强细胞凋亡，从而改善AML的ATRA治疗。APL和AML细胞系，以及原代AML样品，被用来探索ATRA治疗过程中调节分化和凋亡的机制。稳定转染和siRNA基因沉默用于鉴定诱导分化过程中抑制凋亡的关键因子和加速凋亡的药物。在分化反应性AML细胞中，ATRA治疗诱导Bcl-2的持久抑制，同时首先上调然后降低Mcl-1水平。Mcl-1水平似乎是分化和凋亡之间的看门人。在分化诱导过程中，ATRA激活MEK/ERK和PI 3 K/Akt通路导致p90 RSK激活和糖原合成酶激酶3β（GSK 3 β）失活，这通过增加Mcl-1的翻译和稳定性来增加Mcl-1水平。索拉非尼通过逆转p90 RSK激活和GSK 3 β失活阻断ATRA诱导的Mcl-1增加，维持受抑制的Bcl-2水平，并增强非APL AML细胞系和原代AML细胞中ATRA诱导的细胞凋亡。抑制Mcl-1是诱导ATRA分化应答性AML细胞凋亡所必需的。ATRA和索拉非尼可以开发为AML患者的新型药物组合疗法，因为这种药物组合通过抑制Bcl-2和Mcl-1来增加细胞凋亡。
All trans retinoic acid (ATRA) is successful in treating acute promyelocytic leukemia (APL) by inducing terminal differentiation-mediated cell death, but it has limited activity in non-APL acute myeloid leukemia (AML). We aim to improve ATRA therapy of AML by enhancing apoptosis through repression of the anti-apoptotic proteins Bcl-2 and Mcl-1. APL and AML cell lines, as well as primary AML samples, were used to explore the mechanisms regulating differentiation and apoptosis during ATRA treatment. Stable transfection and gene silencing with siRNA were used to identify the key factors that inhibit apoptosis during induction of differentiation and drugs that accelerate apoptosis. In differentiation responsive AML cells, ATRA treatment induces long-lasting repression of Bcl-2 while first up-modulating and then reducing the Mcl-1 level. The Mcl-1 level appears to serve as a gatekeeper between differentiation and apoptosis. During differentiation induction, activation of MEK/ERK and PI3K/Akt pathways by ATRA leads to activation of p90RSK and inactivation of glycogen synthase kinase 3β (GSK3β), which increase Mcl-1 levels by increasing its translation and stability. Sorafenib blocks ATRA-induced Mcl-1 increase by reversing p90RSK activation and GSK3β inactivation, maintains the repressed Bcl-2 level, and enhances ATRA induced apoptosis in non-APL AML cell lines and in primary AML cells. Inhibition of Mcl-1 is required for apoptosis induction in ATRA differentiation responsive AML cells. ATRA and Sorafenib can be developed as a novel drug combination therapy for AML patients because this drug combination augments apoptosis by inhibiting Bcl-2 and Mcl-1.