权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The development of targeted therapies using FKHRL1 for the treatment of leukemia

使用FKHRL1治疗白血病的靶向疗法的开发

基本信息

批准号：
15390306
负责人：
KOMATSU Norio
金额：
$ 9.41万
依托单位：
University of Yamanashi (2004-2005)Jichi Medical University (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390306/
关键词：
FKHRL1 FOXO3a TRAIL APL apoptosis drug-sensitivity autocrine all-trans retinoic acid 慢性骨髄性白血病 imatinib 薬剤耐性 DNAマイクロアレイアポトーシス造血 siRNA トランスジェニックマウス

项目摘要

FKHRL1 (also called FOXO3a) is a member of the FOXO subfamily of Forkhead transcription factors and lies downstream of cytokine signaling pathways. This molecule is phosphorylated by activated Akt/Gsk and remains in the cytoplasm as an "inactive form". In this study, we found that FKHRL1 functions downstream of Bcr-Abl tyrosine kinase as a phosphorylated "inactive" form in chronic myelogenous leukemia (CML). The Bcr-Abl tyrosine kinase inhibitor imatinib induced cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated "inactive" form to the dephosphorylated "active" form in CML-derived cell lines. To examine whether "active" FKHRL1 can overcome the resistance to imatinib, we generated a 4-hydroxytamoxifen (4-OHT)-inducible "active" FKHRL1 (FKHRL1-TM ; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated)-estrogen receptor fusion protein expression system in CML-derived imatinib-resistant cell lines. 4-OHT inhibited the cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, "active" FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines.Moreover, we also found that all-trans retinoic acid (ATRA) induced apoptosis via FKHRL1-mediated TRAIL production in APL-derived cell line NB4 which was sensitive to ATRA. Like CML cells, over-expression of "active" FKHRL1 induced apoptosis not only in ATRA-sensitive cell line NB4 but also in ATRA-resistant NB4R cell line. Therefore, our results suggest that "active" FKHRL1 can overcome imatinib resistance and ATRA resistance in CML and APL cell lines, respectively, in part via TRAIL production.

FKHRL 1（也称为FOXO 3a）是Forkhead转录因子FOXO亚家族的成员，位于细胞因子信号通路的下游。该分子被激活的Akt/Gsk磷酸化，并以“无活性形式”保留在细胞质中。在这项研究中，我们发现FKHRL 1在慢性粒细胞白血病（CML）中作为磷酸化的“非活性”形式在Bcr-Abl酪氨酸激酶下游发挥作用。Bcr-Abl酪氨酸激酶抑制剂伊马替尼通过将CML衍生细胞系中的FKHRL 1从磷酸化的“非活性”形式转化为去磷酸化的“活性”形式，诱导细胞周期停滞和随后的凋亡。为了检查“活性”FKHRL 1是否可以克服对伊马替尼的抗性，我们在CML衍生的伊马替尼抗性细胞系中产生了4-羟基他莫昔芬（4-OHT）诱导的“活性”FKHRL 1（FKHRL 1-TM ; FKHRL 1的三重突变体，其中所有三个Akt磷酸化位点都已突变）-雌激素受体融合蛋白表达系统。4-OHT抑制细胞生长和细胞周期进程，诱导细胞凋亡，并上调肿瘤坏死因子相关凋亡诱导配体（TRAIL）。此外，我们还发现全反式维甲酸（all-transretinoicacid，ATRA）通过FKHRL 1介导的TRAIL产生诱导对ATRA敏感的APL细胞株NB 4的凋亡。与CML细胞一样，过表达“活性”FKHRL 1不仅在ATRA敏感细胞系NB 4中诱导凋亡，而且在ATRA耐药细胞系NB 4 R中也诱导凋亡。因此，我们的研究结果表明，“活性”FKHRL 1可以克服伊马替尼耐药和ATRA耐药的CML和APL细胞系，分别通过部分TRAIL的生产。