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

Fulvio Chiacchiera; Valentina Grossi; Marianna Cappellari; Alessia Peserico; Marta Simonatto; Aldo Germani; Silvana Russo; Mary P Moyer; Nicoletta Resta; Stefania Murzilli; Cristiano Simone

doi:10.1016/j.canlet.2012.05.006

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

Cancer Lett. 2012 Nov 1;324(1):98-108. doi: 10.1016/j.canlet.2012.05.006. Epub 2012 May 11.

Authors

Fulvio Chiacchiera¹, Valentina Grossi, Marianna Cappellari, Alessia Peserico, Marta Simonatto, Aldo Germani, Silvana Russo, Mary P Moyer, Nicoletta Resta, Stefania Murzilli, Cristiano Simone

Affiliation

¹ Laboratory of Signal-Dependent Transcription, Dept. of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy. fulvio.chiacchiera@ieo.eu

PMID: 22579651
DOI: 10.1016/j.canlet.2012.05.006

Abstract

We recently demonstrated that p38α 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 p38α is followed by TRAIL-mediated activation of caspase-8 and FoxO3A-dependent HER3 upregulation with consequent overactivation of the MEK-ERK1/2 survival pathway. p38α 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 p38α inhibition, to develop new approaches for CRC treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Animals
Apoptosis / drug effects
Apoptosis / genetics
Benzamides / pharmacology
Caspase 8 / metabolism
Cell Death / drug effects
Cell Death / genetics
Cell Line, Tumor
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology*
Diphenylamine / analogs & derivatives
Diphenylamine / pharmacology
Enzyme Inhibitors / pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism*
Female
HT29 Cells
Humans
Imidazoles / pharmacology
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 1 / genetics
MAP Kinase Kinase 1 / metabolism
Male
Mice
Mice, Nude
Middle Aged
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / metabolism
Phosphorylation
Pyridines / pharmacology
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Benzamides
Enzyme Inhibitors
Imidazoles
Pyridines
mirdametinib
Diphenylamine
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase 14
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase 1
MAP2K1 protein, human
Caspase 8
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole