FIGURE 8.

Suggested molecular mechanism underlying induction of lethal proteotoxic stress in aurin-exposed malignant melanoma cells. Aurin induces rapid Hsp90 inhibition causing HSF1 nuclear translocation (detectable within minutes of exposure) and pronounced activation of heat shock response gene expression. Together with Hsp90 antagonism, destabilization of Hsp90 client proteins (e.g. oncogenic BRAF and AhR), UPR induction characterized by phosphorylation of PERK and eIF2α and up-regulation of DDIT3 (CHOP), and proteasomal impairment with accumulation of ubiquitinated proteins contribute to aurin-induced proteotoxic stress. Downstream of proteotoxic stress induction (with unknown involvement of transcription factors upstream of PMAIP1 such as ATF4 and p53) Noxa up-regulation facilitates the mitochondrial pathway of apoptosis associated with breakdown of mitochondrial transmembrane potential, induction of massive oxidative stress and glutathione depletion, and ultimately initiation of caspase-dependent cell death. Cell rescue as demonstrated in this study can occur by siRNA-based suppression of PMAIP1 up-regulation, antioxidant intervention (NAC), and pancaspase inhibition (zVADfmk). The molecular mechanism underlying the crucial transition from aurin-induced proteotoxic stress to apoptogenic lethal execution remains to be elucidated.