title: Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models.
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.
authors.affiliation: Laboratory of Signal-Dependent Transcription, Dept. of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy. fulvio.chiacchiera@ieo.eu
authors.forename: Fulvio
authors.initials: F
authors.lastname: Chiacchiera
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.forename: Marianna
authors.initials: M
authors.lastname: Cappellari
authors.forename: Alessia
authors.initials: A
authors.lastname: Peserico
authors.forename: Marta
authors.initials: M
authors.lastname: Simonatto
authors.forename: Aldo
authors.initials: A
authors.lastname: Germani
authors.forename: Silvana
authors.initials: S
authors.lastname: Russo
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048308:Mitogen-Activated Protein Kinase 14; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D053181:Caspase 8; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole