title: MEK/ERK inhibitor U0126 increases the radiosensitivity of rhabdomyosarcoma cells in vitro and in vivo by downregulating growth and DNA repair signals.
abstract: Multimodal treatment has improved the outcome of many solid tumors, and in some cases the use of radiosensitizers has significantly contributed to this gain. Activation of the extracellular signaling kinase pathway (MEK/ERK) generally results in stimulation of cell growth and confers a survival advantage playing the major role in human cancer. The potential involvement of this pathway in cellular radiosensitivity remains unclear. We previously reported that the disruption of c-Myc through MEK/ERK inhibition blocks the expression of the transformed phenotype; affects in vitro and in vivo growth and angiogenic signaling; and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). This study was designed to examine whether the ERK pathway affects intrinsic radiosensitivity of rhabdomyosarcoma cancer cells. Exponentially growing human ERMS, RD, xenograft-derived RD-M1, and TE671 cell lines were used. The specific MEK/ERK inhibitor, U0126, reduced the clonogenic potential of the three cell lines, and was affected by radiation. U0126 inhibited phospho-active ERK1/2 and reduced DNA protein kinase catalytic subunit (DNA-PKcs) suggesting that ERKs and DNA-PKcs cooperate in radioprotection of rhabdomyosarcoma cells. The TE671 cell line xenotransplanted in mice showed a reduction in tumor mass and increase in the time of tumor progression with U0126 treatment associated with reduced DNA-PKcs, an effect enhanced by radiotherapy. Thus, our results show that MEK/ERK inhibition enhances radiosensitivity of rhabdomyosarcoma cells suggesting a rational approach in combination with radiotherapy.
authors.affiliation: Francesco Marampon, Department of Experimental Medicine, Division of Radiotherapy and Radiobiology Laboratory, University of L'Aquila Via Vetoio, Coppito 2, 67100, Italy. L'Aquila. f.marampon@virgilio.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Agnese
authors.initials: A
authors.lastname: Di Rocco
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bonfili
authors.forename: Mario
authors.initials: M
authors.lastname: Di Staso
authors.forename: Caterina
authors.initials: C
authors.lastname: Fardella
authors.forename: Lorella
authors.initials: L
authors.lastname: Polidoro
authors.forename: Carmela
authors.initials: C
authors.lastname: Ciccarelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Popov
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tombolini
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Zani
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011838:Radiation-Sensitizing Agents; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases