MEKs/ERKs inhibitor U0126 increases the radiosensitivity of rhabdomyosarcoma cells in vitro and in vivo by down regulating growth and DNA repair signals

• Published in: Molecular cancer therapeutics 2011-01, Vol.10 (1), p.159-168
• Main Authors: Marampon, Francesco, Gravina, Giovanni Luca, Di Rocco, Agnese, Bonfili, Pierluigi, Di Staso, Mario, Fardella, Caterina, Polidoro, Lorella, Ciccarelli, Carmela, Festuccia, Claudio, Popov, Vladimir M., Pestell, Richard G., Tombolini, Vincenzo, Zani, Bianca Maria
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-10-0631

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, angiogenic signaling, and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). The present 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 effected by radiation. U0126 inhibited phospho/active ERK1/2 and reduced DNAPKcs 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 DNAPKcs, 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.