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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)98-108
Number of pages11
JournalCancer Letters
Volume324
Issue number1
DOIs
Publication statusPublished - Nov 1 2012

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Colorectal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Apoptosis
Cell Death
Growth
Caspase 8
MAP Kinase Signaling System
Autophagy
Caspase 3
Up-Regulation
Pharmacology
In Vitro Techniques
Neoplasms

Keywords

  • Animal models
  • Cell death
  • Colorectal cancer
  • ERK
  • P38

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. / Chiacchiera, Fulvio; Grossi, Valentina; Cappellari, Marianna; Peserico, Alessia; Simonatto, Marta; Germani, Aldo; Russo, Silvana; Moyer, Mary P.; Resta, Nicoletta; Murzilli, Stefania; Simone, Cristiano.

In: Cancer Letters, Vol. 324, No. 1, 01.11.2012, p. 98-108.

Research output: Contribution to journalArticle

Chiacchiera, F, Grossi, V, Cappellari, M, Peserico, A, Simonatto, M, Germani, A, Russo, S, Moyer, MP, Resta, N, Murzilli, S & Simone, C 2012, 'Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models', Cancer Letters, vol. 324, no. 1, pp. 98-108. https://doi.org/10.1016/j.canlet.2012.05.006
Chiacchiera, Fulvio ; Grossi, Valentina ; Cappellari, Marianna ; Peserico, Alessia ; Simonatto, Marta ; Germani, Aldo ; Russo, Silvana ; Moyer, Mary P. ; Resta, Nicoletta ; Murzilli, Stefania ; Simone, Cristiano. / Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. In: Cancer Letters. 2012 ; Vol. 324, No. 1. pp. 98-108.
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