c-Myc Sustains Transformed Phenotype and Promotes Radioresistance of Embryonal Rhabdomyosarcoma Cell Lines.
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.
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
G L
GL
Gravina
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
C
C
Festuccia
b   Department of Radiation Oncology, Perelman School of Medicine, Penn Center for Innovation Fellow, University of Pennsylvania, Philadelphia, Pennsylvania;
V M
VM
Popov
c   Department of Orthopedics/Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.
A
A
Di Rocco
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
A
A
Colapietro
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
P
P
Sanità
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
S Delle
SD
Monache
d   Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
D
D
Musio
d   Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
F
F
De Felice
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
E
E
Di Cesare
d   Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
V
V
Tombolini
a   Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
F
F
Marampon
D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D018233:Rhabdomyosarcoma, Embryonal / Q000473:pathology*
D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering