Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors.
Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors.
复制标题
醛糖还原酶抑制通过AKT/FOXO3A依赖性死亡受体上调，增强了跟踪诱导的人类结肠癌细胞凋亡。
DOI：
10.1016/j.freeradbiomed.2013.05.039
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发表时间：
2013-10
影响因子：
7.4
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
--
作者：
Shoeb, Mohammad;Ramana, Kota V.;Srivastava, Satish K.
与选择性杀死肿瘤细胞的肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）化疗相关的主要问题之一是耐药性降低。这就需要开发能够使肿瘤细胞对 TRAIL 敏感的安全新型药物。在此，我们研究了醛糖还原酶 (AR) 在使癌细胞对 TRAIL 敏感并增强 TRAIL 诱导的人结肠癌细胞凋亡中的作用。我们证明，AR 抑制通过上调死亡受体 (DR)-5 和 DR4 来增强 TRAIL 诱导的癌细胞毒性。 DR5 和 DR4 的敲低显着（>85%）降低 AR 抑制剂的敏化作用。 fidarestat，对 TRAIL 诱导的细胞凋亡。此外，AR 抑制还会下调细胞存活蛋白（Bcl-xL、Bcl-2、survivin、XIAP 和 FLIP）并上调促凋亡蛋白（如 Bax）的表达，并改变线粒体膜电位，导致细胞色素-C 释放、caspases-3 激活和 PARP 裂解。我们发现 AR 抑制调节叉头转录因子 FOXO3a 的 AKT/PI3K 依赖性激活。 FOXO3a 的敲低显着 (>80%) 消除了 AR 抑制诱导的 DR5 和 DR4 上调以及结肠癌细胞凋亡。总体而言，我们的结果表明，fidarestat 通过下调细胞存活蛋白并通过激活 AKT/FOXO3a 途径上调死亡受体来增强 TRAIL 诱导的细胞凋亡。
One of the major problems associated with the chemotherapy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) that selectively kills tumor cells is decreased drug resistance. This warranted the development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL. Here in, we examined the role of aldose reductase (AR) in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. We demonstrate that AR inhibition potentiates TRAIL-induced cytotoxicity in cancer cells by upregulation of both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 significantly (>85%) reduced the sensitizing effect of AR inhibitor. fidarestat, on TRAIL-induced apoptosis. Further, AR inhibition also down-regulates cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, and FLIP) and up-regulates the expression of pro-apoptotic proteins such as Bax and alters mitochondrial membrane potential leading to cytochrome-C release, caspases-3 activation and PARP cleavage. We found that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO3a. Knockdown of FOXO3a significantly (>80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that fidarestat, potentiates TRAIL-induced apoptosis through down-regulation of cell survival proteins and upregulation of death receptors via activation of AKT/FOXO3a pathway.
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影响因子：
11.2
作者：
Prasad S;Yadav VR;Ravindran J;Aggarwal BB
通讯作者：
Aggarwal BB
人类癌症中的磷酸肌醇3-激酶途径：遗传改变和治疗意义。
影响因子：
2.6
作者：
Arcaro A;Guerreiro AS
通讯作者：
Guerreiro AS
影响因子：
3.7
作者：
Ganapathy S;Chen Q;Singh KP;Shankar S;Srivastava RK
通讯作者：
Srivastava RK
影响因子：
8
作者：
Baker, SJ;Reddy, EP
通讯作者：
Reddy, EP
影响因子：
64.8
作者：
Irmler, M;Thome, M;Tschopp, J
通讯作者：
Tschopp, J