Research Paper Volume 14, Issue 20 pp 8221—8242

Figure 17. The molecular mechanisms by which AR12 and neratinib act to degrade the expression of chaperones, Tau, and APP. The initial action of AR12 is to inhibit multiple chaperone ATPase activities, particularly that of GRP78. This causes a modest increase in eIF2α phosphorylation in the endoplasmic reticulum which is responsible for modest increases in the expression of Beclin1 and ATG5. Neratinib, via regulation of small GTP binding proteins, receptors and MST4 causes LAP, resulting in the internalization of plasma membrane GRP78 and the proteins it chaperones, Tau and APP. Inhibition of cytosolic HSP90 and HSP70 also ultimately enhances ER stress signaling and autophagosome formation. Following the initial drug-induced signals that destabilize proteins and promote an ER stress / autophagy response, additional on-going degradation of GRP78 amplifies the initial response causing greater amounts of eIF2α phosphorylation, greater amounts of Beclin1 and ATG5 expression and significantly more autophagosome formation which is associated with autophagic flux. Thus, a self-supporting ER stress / autophagy response is generated that acts to further reduce Tau and APP expression.