Mechanisms of Endoplasmic Reticulum Stress-Mediated Pathways to Apoptosis: Significance for Tumor therapy

Author(s): Abdulaziz M. Eshaq, Thomas W. Flanagan, Mohammed H. Albitar, Nouf Alshammari, Maroa Al Jaberi, Ameer Bakhamees, Raghad Alrasheed, Fatima Alaidaros, Fatima Binyahya, JohnO’Brien, Abdulaziz Bagubair, Youssef Haikel, Mohamed Hassan

The endoplasmic reticulum (ER) acts as a quality control organelle for protein homeostasis. The systems for controlling protein quality include ER-associated degradation, protein chaperones, and autophagy. Disruptions in ER function, a process called ER stress, trigger the unfolded protein response (UPR), a tightly orchestrated series of intracellular signal transduction reactions to restore protein homeostasis. The imbalance between the rate of mRNA translation and the efficiency of protein folding leads to the accumulation of unfolded or misfolded proteins inside the ER lumen which triggers ER stress. UPR is characterized by the action of three signaling proteins: inositol-required protein-1α (IRE1α), protein kinase RNA (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6). The persistence of chronic ER stress and protein load exceeds the ER's capacity, leading to cellular dysfunction and cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributing factor to diseases such as tumors, making modulators of ER stress pathways potentially attractive targets for drug discovery. In this review we focus on the mechanisms of stress-induced pathways to apoptosis and their impact as therapeutic target in cancer treatment.