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Radiat Res. 2016 Apr;185(4):411-22. doi: 10.1667/RR14237.1.

c-Myc Sustains Transformed Phenotype and Promotes Radioresistance of Embryonal Rhabdomyosarcoma Cell Lines.

Author information

1
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
2
b   Department of Radiation Oncology, Perelman School of Medicine, Penn Center for Innovation Fellow, University of Pennsylvania, Philadelphia, Pennsylvania;
3
c   Department of Orthopedics/Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.
4
d   Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Abstract

We have previously reported that the MEK/ERK pathway sustains in vitro and in vivo transformed phenotype and radioresistance of embryonal rhabdomyosarcoma (ERMS) cell lines. Furthermore, we found that aberrant MEK/ERK signaling activation promotes c-Myc oncoprotein accumulation. In this study, the role of c-Myc in sustaining the ERMS transformed and radioresistant phenotype is characterized. RD and TE671 cell lines conditionally expressing MadMyc chimera protein, c-Myc-dominant negative and shRNA directed to c-Myc were used. Targeting c-Myc counteracted in vitro ERMS adherence and in suspension, growth motility and the expression of pro-angiogenic factors. c-Myc depletion decreased MMP-9, MMP-2, u-PA gelatinolytic activity, neural cell adhesion molecule sialylation status, HIF-1α, VEGF and increased TSP-1 protein expression levels. Rapid but not sustained targeting c-Myc radiosensitized ERMS cells by radiation-induced apoptosis, DNA damage and impairing the expression of DNA repair proteins RAD51 and DNA-PKcs, thereby silencing affected ERMS radioresistance. c-Myc sustains ERMS transformed phenotype and radioresistance by protecting cancer cells from radiation-induced apoptosis and DNA damage, while promoting radiation-induced DNA repair. This data suggest that c-Myc targeting can be tested as a promising treatment in cancer therapy.

PMID:
27104757
DOI:
10.1667/RR14237.1
[Indexed for MEDLINE]

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