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.