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.

Transcriptional Repression of Mad-Max Complex by Human Umbilical Cord Blood Stem Cells Downregulates Extracellular Signal-Regulated Kinase in Glioblastoma

“…Immunohistochemical staining of the tissue sections from control and hUCBSC-treated mice have shown that hUCBSC not only downregulates ERK but also its active form pERK. In line with our findings, U0126 treatment in embryonal rhabdomyosarcoma tumors downregulated phosphoactive ERK, c-Myc, and cyclin D1, suggesting the role of ERK in reducing c-Myc and cyclin D1 activity [24].…”

“…c-Myc and Ras/MEK/ERK pathways play important roles in the progression of the G 1 -cell cycle phase [24,36,37] by enhancing cyclin expression and CDK/cyclin complex activities [38]. Use of U0126, a MEK/ERK pathway inhibitor, demonstrates the role of ERK in promoting G1 cell cycle arrest [39].…”

Phenylpropanoids in radioregulation: double edged sword

“…Many radiosensitizing agents have been investigated to inhibit IR-induced activation of specific intracellular molecules, which play a role in anti-apoptotic, prosurvival, and proliferative signaling, such as ErbB family of receptor tyrosine kinases, Ras, Akt, and MAPKs, then leading to cancer cell death (GanaWeisz et al, 2002;Nyati et al, 2004;Fujiwara et al, 2007;Marampon et al, 2011). The radioprotective agents, including the sulfhydryl compounds and WR-2721 (amifostine), have been also suggested to protect from IR-induced damage by scavenging of free radicals (Patt et al, 1949;Yuhas et al, 1980).…”

The kinome pathways in radioresistance breast cancer stem cells

“…From this point, researchers have been found that the radioresistance is made by prosurvival genes induced by signaling pathways including protein kinases and transcription factors (8,9).…”

“…However, Guo et al has found there are common pathways which are up and down regulated in the two cell lines which suggested by the author that have other cellular pathways. Marampon et al (9) showed that activation of signaling kinase pathways (MERK/ERK) result in radioresistance and inhibit these kinases pathways will enhance radiosensitive. Other groups had provided an evidence that HER2 (Her2+/CD44+/CD24−/ low ) mediate prosurvival signals and overexpressing BCSCs is the mediator for aggressive phenotype and radioresistance (10,11) in addition there are many studies suggest the correlation between ERBB inhibition and radiosensitive (12)(13)(14), which is inconsistence with Guo et al data, he revealed that ERBB signal is downregulated or inhibited in MCF7/C6 which is radioresistance cell line compare to MCF7/Wt.…”