Abstract 1198: Adaptation to ER stress as a driver of increased expression of Mcl-1 with melanoma progression

Past studies have shown that Mcl-1 expression increases with melanoma progression, which is an important mechanism of resistance of melanoma cells to apoptosis. We show here that up-regulation of Mcl-1 in melanoma is a consequence of adaptation of melanoma cells to endoplasmic reticulum (ER) stress. Exposure of cultured melanoma cells and fresh melanoma isolates to pharmacological ER stress inducers results in up-regulation of Bcl-2 and Mcl-1. Inhibition of Mcl-1 renders melanoma cells more sensitive to ER stress-induced apoptosis even when Bcl-2 is over-expressed, but inhibition of Bcl-2 does not increase the sensitivity to ER stress-induced apoptosis in melanoma cells over-expressing Mcl-1. Up-regulation of Mcl-1 by ER stress involves multiple mechanisms. The transcriptional increase is mediated by the transcription factor ETS-1 downstream of the XBP1 axis of the unfolded protein response, whereas down-regulation of GSK3α is responsible for reduced proteasomal degradation of Mcl-1 in melanoma cells under ER stress. Studies on a large cohort of melanocytic tumor tissue sections revealed that expression of GRP78, a classic marker of ER stress, and expression of LDH5, an indicator of hypoglycemia that is one of the causes of ER stress, correlate with Mcl-1 expression, indicating that the increase in Mcl-1 with melanoma progression in vivo is associated with ER stress. In addition, we demonstrate in this report that induction of apoptosis by ER stress in melanoma cells deficient in Mcl-1 is mediated by the BH3-only proteins PUMA and Noxa, whereas another BH3-only protein Bim does not appear to play a part in melanoma cells as it does in other cell types. In summary, our results indicate that adaptation to ER stress is a driver of up-regulation of Mcl-1 during progression of melanoma, and suggest that strategies aimed at inhibiting the activity of Mcl-1 may be important in the treatment of melanoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1198.