1. ¹INSERM U590 "Oncogenèse et Progression Tumorale", Lyon cedex 08, Lyon, France
2. ²Université Claude Bernard Lyon I, Lyon cedex 08, France
3. ³Centre Léon Bérard, Lyon cedex 08, Lyon, France

Correspondence: Dr Thibault Voeltzel, INSERM U590, Centre Léon Bérard, 28 rue Laënnec, Lyon cedex 08 69373, France. E-mail: voeltzel@lyon.fnclcc.fr

Received 30 January 2007; Revised 30 April 2007; Accepted 14 May 2007; Published online 16 August 2007.

Abstract

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