Gadd45a activation protects melanoma cells from ultraviolet B-induced apoptosis.
Epidemiological and biological studies indicate that solar UVB radiation is involved in cutaneous malignant melanoma etiology. Indeed, melanocytes are very frequently exposed to solar UV radiation, which induces cell damage and may promote cell transformation. We previously showed that melanocytes and melanoma cells exposed to UVB radiation activates a p53-independent pathway involving Gadd45a and, more recently, that Gadd45a plays a critical role in UVB-induced G2 cell cycle arrest of melanoma cells. In this study, we demonstrate that the inhibition of UV-induced Gadd45a overexpression by RNA interference results in a dramatic increase of cell death. We identify this cell death as apoptosis, with activation of Caspase-3 and a decrease in Bcl-x(L) expression. Furthermore, we show that inhibition of UV-induced Gadd45a overexpression also leads to increased sensitivity of melanoma cells to therapeutic agents such as DTIC and Cisplatin. We conclude that UVB-induced Gadd45a overexpression protects melanoma cells from apoptosis, both by causing a G2 cell cycle arrest and by inhibiting the mitochondrial apoptotic pathway. These observations suggest that Gadd45a inactivation could be a useful way to sensitize melanoma cells to chemotherapy. JID journal club article: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub
Fayolle
Caroline
C
INSERM U590 Oncogenèse et Progression Tumorale, Lyon cedex 08, Lyon, France.
Pourchet
Julie
J
Caron de Fromentel
Claude
C
Puisieux
Alain
A
Doré
Jean-François
JF
Voeltzel
Thibault
T
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D053148:Caspase 3 / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008544:Melanocytes / Q000528:radiation effects*; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000032:analysis; D000097642:GADD45 Proteins
D053148:Caspase 3; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D051020:bcl-X Protein; C439070:GADD45A protein, human; D000097642:GADD45 Proteins