Thiazolidinedione (TZD) binds to nuclear transcriptional factor PPAR-gamma, thereby causing metabolic reprogramming. This drug for the treatment for insulin resistance in type-II DM has been modified into HA15, the novel compound leading ER stress by directly and specifically binding with BiP, also referred to as GFP78. This is the typical case of drug repositioning. Here, HA15 has been shown to promote the dissociation of the ER stress-related molecule complex composed of PERK, IRE1-alpha, and ATF4, therefore reducing the ATPase activity of BiP, which is responsible for the attenuated UPR potential. In addition to the fact that HA15 can overcome the therapeutic limitations against BRAF inhibitor-resistant melanoma cells, they do not at all affect the cellular viability of human normal fibroblasts or melanocytes. It is notable that they also harbor the similar ER stress machinery, but BiP in the normal cells does not seem to be disturbed. What is the difference of BiP (GRP78) between normal and malignant cells in the regulation of ER stress?? Si-RNA-mediated BiP depletion would be the useful experimental design?
http://www.cell.com/cancer-cell/abstract/S1535-6108(16)30171-4
It might be a cell type dependent effect. For example, the cellular activities (for eg. stage of cell cycle, quiescence or proliferative), protein synthesis rates, hypoxia, calcium homeostatic mechanisms and oxidative stress vary between normal and cancer cells. Such variations could influence the threshold for ER stress induction and control the balance between cytoprotective and cell death signaling pathways.
Hi Go,
Physiologically, GRP78 is a protein chaperone that maintains proper protein folding. Under normal conditions, GRP78 is normally found bound to ER membrane proteins, PERK, IRE1, and ATF6, keeping these proteins in an inactive state. When cellular events occurs, as Muruganandan Shanmugam addressed, GRP78 dissociates and allows each of PERK and IRE1 subunits to undergo homodimerization and ATF6 cleavage. This process activates the unfolded protein response.
However, there is a strange paradigm shift that is currently occurring in today's literature. In conditions of cancer, GRP78 is somehow able to escape the ER and relocate itself to the cell surface. It can associate itself with other cell surface receptors. Furthermore, auto-antibodies against GRP78 is able to trigger intracellular signalling.
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