Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway.
Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway.
复制标题
双去甲氧基姜黄素通过线粒体功能障碍和 GRP78 依赖性途径在人胰腺腺癌细胞中发挥促凋亡作用
DOI：
10.18632/oncotarget.13272
复制
发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Yang H;Fan S;An Y;Wang X;Pan Y;Xiaokaiti Y;Duan J;Li X;Tie L;Ye M;Li X
胰腺癌是一种高度侵袭性的恶性肿瘤，本质上对当前的化疗具有耐药性。在此，我们调查是否双脱甲氧基姜黄素（BDMC），姜黄素的衍生物，增强吉西他滨在人胰腺癌细胞。结果表明，BDMC通过诱导PANC-1和MiaPaCa-2胰腺癌细胞中的线粒体功能障碍和细胞凋亡来增敏吉西他滨。利用二维凝胶电泳和质谱，我们确定了13个重要的蛋白质与显着改变的表达，单独或结合BDMC吉西他滨。蛋白质-蛋白质相互作用网络分析指出葡萄糖调节蛋白78（GRP 78）是由BDMC激活的关键枢纽。我们发现BDMC通过eIF 2 α/CHOP途径上调GRP 78并促进细胞凋亡。此外，在PANC-1细胞中，吉西他滨增加了DJ-1和抑制素（两种鉴定的化学抗性标志物）。这可以被BDMC有意义地逆转，表明BDMC部分抵消了吉西他滨诱导的化疗耐药性。总之，这些发现表明，BDMC通过GRP 78依赖性途径和线粒体功能障碍促进细胞凋亡，并增强吉西他滨在人胰腺癌细胞中的抗肿瘤作用。
Pancreatic cancer is a highly aggressive malignancy, which is intrinsically resistant to current chemotherapies. Herein, we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggests that BDMC sensitizes gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC-1 and MiaPaCa-2 pancreatic cancer cells. Utilizing two-dimensional gel electrophoresis and mass spectrometry, we identify 13 essential proteins with significantly altered expressions in response to gemcitabine alone or combined with BDMC. Protein-protein interaction network analysis pinpoints glucose-regulated protein 78 (GRP78) as the key hub activated by BDMC. We then reveal that BDMC upregulates GRP78 and facilitates apoptosis through eIF2α/CHOP pathway. Moreover, DJ-1 and prohibitin, two identified markers of chemoresistance, are increased by gemcitabine in PANC-1 cells. This could be meaningfully reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In summary, these findings show that BDMC promotes apoptosis through a GRP78-dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.