Endoplasmic Reticulum Stress
A cellular condition where the endoplasmic reticulum (the organelle responsible for protein folding and processing) becomes overwhelmed by misfolded proteins. ER stress triggers the unfolded protein response and can lead to apoptosis. Proteasome inhibitors (bortezomib, carfilzomib) cause ER stress in cancer cells.
Technical Context
The ER is responsible for protein folding, quality control, and secretion. ER stress occurs when: unfolded/misfolded protein load exceeds folding capacity (caused by: nutrient deprivation, hypoxia, calcium depletion, viral infection, or proteasome inhibition preventing misfolded protein clearance). The unfolded protein response (UPR) is activated through three sensors: IRE1α (→ XBP1 splicing → ER chaperone upregulation), PERK (→ eIF2α phosphorylation → global translation attenuation + ATF4 activation), and ATF6 (→ cleaved → ER chaperone/ERAD gene transcription). If the UPR fails to restore homeostasis, pro-apoptotic signalling is activated (CHOP transcription factor → BCL-2 family modulation → mitochondrial apoptosis pathway). Proteasome inhibitors (bortezomib, carfilzomib) exploit this: myeloma cells' massive immunoglobulin production generates extreme ER protein folding demand; blocking proteasomal clearance of misfolded proteins overwhelms the UPR → terminal ER stress → apoptosis. Normal cells tolerate proteasome inhibition better because of lower protein synthesis rates.