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A number of cellular stress conditions, such as nutrient deprivation, hypoxia, alterations in glycosylation status, and disturbances of calcium flux, lead to accumulation and aggregation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen and cause so-called ER stress. The ER responds to the stress conditions by activation of a range of stress-response signalling pathways to alter transcriptional and translational programs, which couples the ER protein folding load with the ER protein folding capacity and is termed the unfolded protein response (UPR). The UPR of mammalian cells is initiated by three ER transmembrane proteins activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) and double-stranded RNAactivated protein kinase-like ER kinase (PERK) that act as proximal sensors of ER stress. Under unstressed conditions, the luminal domains of these sensors are occupied by the ER chaperone glucose-regulated protein 78 (GRP78). Upon ER stress, sequestration of GRP78 by unfolded proteins activates these sensors by inducing phosphorylation and homodimerization of IRE1 and PERK, and relocalization of ATF6 to the Golgi where it is cleaved by Site 1 and Site 2 proteases (S1P and S2P) leading to its activation as a transcriptional factor. The UPR is fundamentally a cyto-protective response, but excessive or prolonged UPR can result in cell death, predominantly by induction of apoptosis. Nevertheless, most melanoma cell lines are insensitive, relative to cultured melanocytes and fibroblasts, to apoptosis induced by pharmacological ER stress inducers, suggesting that melanoma cells may have developed adaptive mechanisms to counteract the apoptosisinducing outputs of the UPR, thus surviving ER stress conditions. This is supported by increased expression of GRP78, a commonly used indicator of activation of the UPR, in melanoma cells in vivo, which is associated with progression of the disease. It is conceivable that, like many other solid cancers, melanoma cells in a developing tumour without sufficient blood supply may undergo hypoxia, nutrient starvation and acidosis. In addition, accumulation of mutant proteins and increased glycolytic activity in cancer cells may also contribute to ER stress. How the UPR switches between the pro-survival and pro-apoptotic signalling pathways remains a dilemma. It is conceivable that adaptive processes converge on mechanisms that

Adaptation to ER Stress as a Mechanism of Resistance of Melanoma to Treatment