Abstract #3275: Up-regulation of Mcl-1 via XBP1-mediated activation of Akt is critical for survival of melanoma cells upon ER stress

A number of BH3-only proteins of the Bcl-2 family have been shown to be activated by endoplasmic reticulum (ER) stress and contribute to ER stress-induced apoptosis in various cell types. However, most human melanoma cell lines are insensitive to ER stress-induced cell death, indicating that the apoptosis-inducing potential of BH3-only proteins is inhibited in melanoma cells when submitted to ER stress. We show in this report that up-regulation of the anti-apoptotic Bcl-2 family protein Mcl-1 is critical in protection of melanoma cells upon ER stress by neutralizing the BH3-only proteins PUMA and Noxa. The latter are also up-regulated by ER stress. Inhibition of Mcl-1 by shRNA rendered melanoma cells sensitive to ER stress-induced apoptosis, but the sensitization was partially reversed by siRNA knockdown of PUMA or Noxa. Up-regulation of PUMA and Noxa was mediated by both p53-dependent and -independent transcriptional mechanisms. Similarly, up-regulation of Mcl-1 was also due to increased transcription that was mediated, at least in part, by induction of activation of Akt downstream of the IRE1/XBP1 signaling pathway of the unfolded protein response (UPR). Taken together, these results reveal the mechanisms by which melanoma cells acquire resistance to apoptosis mediated by BH3-only proteins under ER stress, and identify up-regulation of Mcl-1 as an important adaptive mechanism by which melanoma cells survive ER stress conditions. Therefore, targeting Mcl-1 may improve treatment results of clinically available chemotherapeutic drugs and those in development for clinical use that can induce ER stress in melanoma cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3275.