Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models
Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models
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DOI：
10.1016/j.canlet.2012.05.006
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发表时间：
2012-11-01
期刊：
影响因子：
9.7
通讯作者：
Simone, Cristiano
中科院分区：
文献类型：
--
作者：
Chiacchiera, Fulvio;Grossi, Valentina;Simone, Cristiano
我们最近证明，p38 α是维持结直肠癌（CRC）代谢所必需的，因为它的抑制导致FoxO 3A激活，自噬，细胞死亡和肿瘤生长减少在体外和体内。在这里，我们表明，抑制p38 α后，TRAIL介导的激活caspase-8和FoxO 3A依赖性HER 3上调，随之过度激活MEK-ERK 1/2生存途径。p38 α和MEK联合抑制通过使TRAIL信号传导通过t-Bid和半胱天冬酶-3传播而特异性诱导细胞凋亡，并促进CRC细胞和临床前小鼠模型中的细胞死亡。因此，可以利用目前的MEK 1导向的药理学策略，结合p38 α抑制，开发CRC治疗的新方法。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
We recently demonstrated that p38 alpha is required to maintain colorectal cancer (CRC) metabolism, as its inhibition leads to FoxO3A activation, autophagy, cell death, and tumor growth reduction both in vitro and in vivo. Here we show that inhibition of p38 alpha is followed by TRAIL-mediated activation of caspase-8 and FoxO3A-dependent HER3 upregulation with consequent overactivation of the MEK-ERK1/2 survival pathway. p38 alpha and MEK combined inhibition specifically induces apoptosis by enabling TRAIL signaling propagation through t-Bid and caspase-3, and fosters cell death in CRC cells and preclinical mouse models. Current MEK1-directed pharmacological strategies could thus be exploited, in combination with p38 alpha inhibition, to develop new approaches for CRC treatment. (C) 2012 Elsevier Ireland Ltd. All rights reserved.