...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular Cancer >Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia
【24h】

Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia

机译：靶向Vav3癌基因通过抑制慢性缺氧状态下LNCaP前列腺癌细胞中的雄激素受体磷酸化来增强多西他赛诱导的细胞凋亡

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Background The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA ( siRNA ) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). Methods We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase ( PI3K )/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. Results Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. Conclusions Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K /Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.
机译：背景Rho / Rac鸟苷核苷酸交换因子的Vav家族在哺乳动物细胞中包含三个成员。 Vav3在前列腺癌发展为雄激素非依赖性过程中增强雄激素受体（AR）活性。我们在慢性缺氧（LNCaPH）下检查了Vav3小干扰RNA（siRNA）对多西他赛治疗的LNCaP细胞中细胞增殖和凋亡的影响。方法我们通过细胞增殖，流式细胞术，DNA片段化和免疫印迹分析，研究了Vav3 siRNA（si-Vav3）和多西紫杉醇对慢性缺氧条件下细胞生长和凋亡的单独和联合作用。为了阐明si-Vav3-和多西他赛诱导的细胞凋亡的分子基础，我们分析了磷脂酰肌醇3-激酶（PI3K）/ Akt，细胞外信号调节激酶（ERK），c-jun N末端激酶（JNK）， LNCaPH细胞中使用激酶抑制剂的AR和AR途径。通过肿瘤生长延迟评估了si-Vav3 / atelocollagen复合物单独或与多西他赛联合使用对裸鼠异种移植的影响。结果与常氧下相比，在LNCaPH中观察到Vav3过表达。与单独使用多西他赛通过抑制Akt和ERK磷酸化所诱导的相比，使用siRNA中断Vav3信号增强了多西他赛诱导的细胞生长抑制，从而导致AR磷酸化抑制。除了响应多西紫杉醇通过JNK信号传导增加的B细胞淋巴瘤2（Bcl-2）磷酸化外，si-Vav3还增强了多西紫杉醇诱导的细胞凋亡，其特征在于亚G1期细胞的蓄积和DNA片段化通过Bcl- xL / Bcl-2相关的死亡启动子（Bad）脱磷酸化，导致caspase-9，caspase-3增加，并切割了多聚ADP-核糖聚合酶。 si-Vav3 / atelocollagen复合物注射对异种移植物的肿瘤生长有轻微的抑制作用，si-Vav3 / atelocollagen复合物和多西他赛的组合使用比单独使用多西他赛产生的作用更大。结论中断Vav3信号通过抑制PI3K / Akt，ERK和AR信号通路，增强多西他赛诱导的LNCaP细胞在慢性缺氧条件下的凋亡。与多西他赛联合使用针对Vav3的疗法可能对管理去势抵抗性前列腺癌有实际意义。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号