CBP-mediated FOXO-1 acetylation inhibits pancreatic tumor growth by targeting SirT.
CBP-mediated FOXO-1 acetylation inhibits pancreatic tumor growth by targeting SirT.
复制标题
DOI：
10.1158/1535-7163.mct-13-0863
复制
发表时间：
2014-03
影响因子：
5.7
通讯作者：
Srivastava SK
中科院分区：
文献类型：
--
作者：
Pramanik KC;Fofaria NM;Gupta P;Srivastava SK
在这里，我们研究了辣椒素介导的胰腺癌细胞凋亡的潜在机制。辣椒素处理使 BxPC-3、AsPC-1 和 L3.6PL 细胞中的 JNK、FOXO1 和 BIM 磷酸化。 BIM 的表达因辣椒素处理而增加。辣椒素处理导致 caspase-3 和 PARP 裂解，表明细胞凋亡。抗氧化剂钛试剂和 PEG-过氧化氢酶可阻断辣椒素介导的 JNK/FOXO/BIM 激活并保护细胞免于凋亡。此外，辣椒素处理导致 FOXO-1 的核表达稳定增加，从而导致 DNA 结合增加。发现辣椒素介导的 BIM 表达直接依赖于 FOXO-1 的乙酰化。辣椒素处理后 CBP 的表达增加，而 SirT-1 的表达减少。使用乙酰化模拟物或有缺陷的突变体，我们的结果证明 FOXO-1 的磷酸化是通过辣椒素处理的乙酰化介导的。 JNK 抑制剂减弱了 FOXO-1 的磷酸化、BIM 的激活并消除了辣椒素诱导的细胞凋亡。此外，通过 siRNA 沉默 FOXO1 可以阻断辣椒素介导的 BIM 激活和细胞凋亡，而 FOXO-1 的过度表达则增强了其作用。沉默 Bim 大大减少了辣椒素介导的 caspase-3 和 PARP 裂解，表明 BIM 在细胞凋亡中的作用。口服5mg/kg辣椒素显着抑制无胸腺裸鼠中BxPC-3肿瘤异种移植物的生长。经辣椒素处理的小鼠肿瘤显示 JNK、FOXO-1、BIM 磷酸化和 CBP 水平增加，caspase-3、PARP 裂解，SirT-1 表达减少。综上所述，我们的结果表明辣椒素激活 JNK 和 FOXO-1，通过 CBP 和 SirT-1 导致 FOXO-1 乙酰化。乙酰化 FOXO1 通过 BIM 激活诱导胰腺癌细胞凋亡。
Here we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated JNK, FOXO1 and BIM in BxPC-3, AsPC-1 and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3and PARP indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, capsaicin treatment caused a steady increase in the nuclear expression of FOXO-1 leading to increased DNA binding. Capsaicin-mediated expression of BIM was found to be directly dependent on the acetylation of FOXO-1. The expression of CBP was increased whereas SirT-1was reduced by capsaicin treatment. Using acetylation mimic or defective mutants, our result demonstrated that phosphorylation of FOXO-1 was mediated through acetylation by capsaicin treatment. JNK inhibitor attenuated the phosphorylation of FOXO-1, activation of BIM and abrogated capsaicin-induced apoptosis. Moreover, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis whereas overexpression of FOXO-1augmented its effects. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP, indicating the role of BIM in apoptosis. Oral administration of 5mg/kg capsaicin substantially suppressed the growth of BxPC-3 tumor xenografts in athymic nude mice. Tumors from capsaicin-treated mice showed an increase in the phosphorylation of JNK, FOXO-1, BIM, and levels of CBP, cleavage of caspase-3, PARP and decreased SirT-1 expression. Taken together, our results suggest that capsaicin activated JNK and FOXO-1, leading to the acetylation of FOXO-1 through CBP and SirT-1. Acetylated FOXO1 induced apoptosis in pancreatic cancer cells through BIM activation.