Fenretinide-induced apoptosis via endoplasmic reticulum stress- new targets for melanoma therapy?

Fenretinide, a synthetic derivative of retinoic acid, induces apoptosis of neuroectodermal tumour cells including melanoma. The signalling mechanism of fenretinide-induced apoptosis is mediated by ceramide accumulation with subsequent metabolism to the diasialoganglioside GD3, resulting in oxidative stress, ROS generation through increased 12-lipoxygenase activity, and induction of the DNA damage-inducible transcription factor GADD153. GADD153 induction is also a hallmark of apoptosis induced by endoplasmic reticulum (ER) stress. Since ER stress-induced apoptosis is a potential target pathway for therapy of melanoma, resistant to apoptosis mediated by death receptor ligation or DNA damage, we have tested the hypothesis that fenretinide-induced apoptosis of melanoma results from ER stress. In SK Mel 110 and A375 melanoma cells, fenretinide induced phosphorylation of the translational initiation factor eIF2a, and splicing of Xbp-I; these are both key markers of the unfolded protein response to ER stress. Several ER stress response genes were also induced including Gadd153, Grp78, calnexin and calreticulin. We have also found thet ERp57 and ERdj5, two genes forming part of the protein folding machinery of the ER, are induced in response to fenretinide. siRNA-mediated knockdown of these two gene increased the susceptibility of melanoma cells to fenretinide-induced apoptosis. These results suggest therefore, that targeting mechanisms protecting against ER stress in combination with ER stress-inducing agents such as fenretinide may define a novel and more effective therapeutic strategy for melanoma