Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia.
Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia.
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DOI：
10.1186/1476-4598-12-27
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发表时间：
2013-04-08
期刊：
影响因子：
37.3
通讯作者：
Mimata H
中科院分区：
文献类型：
--
作者：
Nomura T;Yamasaki M;Hirai K;Inoue T;Sato R;Matsuura K;Moriyama M;Sato F;Mimata H
Rho/Rac鸟苷酸交换因子Vav家族在哺乳动物细胞中包含三个成员。在前列腺癌进展为雄激素非依赖的过程中，Vav3增强雄激素受体（AR）的活性。我们研究了Vav3小干扰RNA（siRNA）在慢性缺氧（LNCaPH）条件下对多西他赛处理的LNCaP细胞增殖和凋亡的影响。
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）和多西他赛在慢性缺氧条件下对细胞生长和凋亡的单独及联合作用。为了阐明si - Vav3和多西他赛诱导凋亡的分子基础，我们在LNCaPH细胞中使用激酶抑制剂分析了磷脂酰肌醇3 - 激酶（PI3K）/Akt、细胞外信号调节激酶（ERK）、c - jun N - 末端激酶（JNK）和AR通路的变化。通过肿瘤生长延迟评估了si - Vav3/去端肽胶原复合物单独或与多西他赛联合对裸鼠移植瘤的影响。
与常氧条件下的表达相比，在LNCaPH中观察到Vav3过表达。与单独使用多西他赛相比，使用siRNA阻断Vav3信号通过抑制Akt和ERK磷酸化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。除了多西他赛通过JNK信号传导增加B细胞淋巴瘤2（Bcl - 2）磷酸化外，si - Vav3通过Bcl - xL/Bcl - 2相关死亡促进因子（Bad）去磷酸化增强了多西他赛诱导的凋亡，其特征为亚G1期细胞积累和DNA片段化，从而导致caspase - 9、caspase - 3和裂解的多聚（ADP - 核糖）聚合酶激活增加。si - Vav3/去端肽胶原复合物注射对移植瘤生长有轻微抑制作用，si - Vav3/去端肽胶原复合物与多西他赛联合使用比单独使用多西他赛效果更显著。
阻断Vav3信号通过抑制PI3K/Akt、ERK和AR信号通路，增强了慢性缺氧条件下LNCaP细胞中多西他赛诱导的凋亡。针对Vav3与多西他赛联合的治疗可能对去势抵抗性前列腺癌的治疗具有实际意义。
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). 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. 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. 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.
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影响因子：
4.8
作者：
Isaacs, JS;Jung, YJ;Neckers, LM
通讯作者：
Neckers, LM
影响因子：
4.8
作者：
Deng, XM;Xiao, L;May, WS
通讯作者：
May, WS
影响因子：
158.5
作者：
CRAWFORD, ED;EISENBERGER, MA;GOODMAN, PJ
通讯作者：
GOODMAN, PJ
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.90.19.8910
发表时间：
1993-10-01
影响因子：
11.1
作者：
BERGES, RR;FURUYA, Y;ISAACS, JT
通讯作者：
ISAACS, JT