Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models

被引：54

作者：

Chiacchiera, Fulvio ^{[1
]}

Grossi, Valentina ^{[1
]}

Cappellari, Marianna ^{[1
]}

Peserico, Alessia ^{[1
]}

Simonatto, Marta ^{[2
,3
]}

Germani, Aldo ^{[1
]}

Russo, Silvana ^{[4
]}

Moyer, Mary P. ^{[5
]}

Resta, Nicoletta ^{[6
]}

Murzilli, Stefania ^{[7
,8
]}

Simone, Cristiano ^{[1
,6
]}

机构：

[1] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Lab Signal Dependent Transcript, I-66030 Santa Maria Imbaro, CH, Italy

[2] IRCCS Fdn Santa Lucia, Dulbecco Telethon Inst, I-00143 Rome, Italy

[3] European Brain Res Inst, I-00143 Rome, Italy

[4] Univ Bari, Dept Pathol Anat, I-70124 Bari, Italy

[5] INCELL Corp, San Antonio, TX 78249 USA

[6] Univ Bari, DIM, Div Med Genet, I-70124 Bari, Italy

[7] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Lab Lipid Metab & Canc, I-66030 Santa Maria Imbaro, CH, Italy

[8] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Anim Care Facil, I-66030 Santa Maria Imbaro, CH, Italy

来源：

CANCER LETTERS | 2012年 / 324卷 / 01期

关键词：

Colorectal cancer; Cell death; p38; ERK; Animal models; ACTIVATED PROTEIN-KINASE; MAPK SIGNALING PATHWAYS; DEPENDENT REGULATION; CELL PROLIFERATION; AMPK-FOXO3A AXIS; HUMAN BREAST; P38-ALPHA; COLON; INHIBITORS; MUTATIONS;

D O I：

10.1016/j.canlet.2012.05.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：98 / 108

页数：11

共 48 条

[1]

Computational Identification of a p38SAPK-Regulated Transcription Factor Network Required for Tumor Cell Quiescence [J].