Mcl-1 blocks radiation-induced apoptosis and inhibits clonogenic cell death.
BACKGROUND
Anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-x, can modulate radio- and/or chemosensitivity of human malignancies. Since no information is available on the role Mcl-1 may play in the radioresponse of tumor cells, the relationship between Mcl-1 expression and response to ionizing radiation (IR) was investigated using an antisense strategy.


METHODS
Human melanoma cells were treated with Mcl-1 antisense oligonucleotides (ASOs) and IR. The effects of antisense treatment alone or in combination with IR on proliferation, induction of apoptosis and clonogenic cell death were evaluated.


RESULTS
ASO treatment in combination with IR reduced the mean cell numbers 9.5-fold compared to a 2.6-fold reduction after ASO treatment alone and a 1.6- fold reduction after IR alone. The percentages of apoptosis measured (means +/- SD) were 49% +/- 3.0 in antisense/IR-treated cultures compared to 1.3% +/- 0.5, 14.3% +/- 0.5, 7.3% +/- 1.1 and 10.3% +/- 0.6 in ASO controls, in antisense-treated, in IR-treated and in antisense control plus IR-treated cells, respectively. Colony formation assays demonstrated a synergistic effect of Mcl-1 down-regulation with IR.


CONCLUSIONS
Mcl-1 expression affects the radioresistance of human melanoma cells.
Skvara
Hans
H
Department of Radiotherapy and Radiobiology, University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Thallinger
Christiane
C
Wacheck
Volker
V
Monia
Brett P
BP
Pehamberger
Hubert
H
Jansen
Burkhard
B
Selzer
Edgar
E
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D016923:Cell Death / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011836:Radiation Tolerance; D014162:Transfection
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2