THE RELATIONSHIP BETWEEN CANCER AND ENDOPLASMIC RETICULUM STRESS-INDUCED APOPTOSIS

The endoplasmic reticulum (ER) plays a central role in critical cellular processes such as protein synthesis, folding, and lipid biosynthesis. ER stress is triggered by the accumulation of misfolded proteins and activates the Unfolded Protein Response (UPR) pathways to ensure cell survival. The UPR attempts to restore ER homeostasis through sensors such as PKR-like ER Kinase (PERK), Inositol-Requiring Enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6). However, prolonged or severe ER stress can lead to cell death by triggering apoptosis. In cancer cells, factors such as hypoxia, nutrient deprivation, and oxidative stress in the tumor microenvironment contribute to chronic ER stress. Under these conditions, activation of the UPR supports cancer cell survival, while excessive ER stress can induce apoptosis. The role of ER stress and the UPR in cancer progression is complex due to their dual effects in both promoting tumor growth and triggering apoptosis. For instance, the IRE1α-X-Box Binding Protein 1 (XBP1) and PERK-Eukaryotic Translation Initiation Factor 2α (eIF2α)- Activating Transcription Factor 4 (ATF4) pathways can enhance survival and chemoresistance in cancer cells, while pro-apoptotic signals such as C/EBP Homologous Protein (CHOP) and c-Jun N-Terminal Kinase (JNK) can trigger cell death. Understanding this balance offers new targets for cancer therapy. Proteasome inhibitors and other agents that increase ER stress have therapeutic potential by inducing apoptosis in cancer cells. This review examines the molecular mechanisms of ER stress, the UPR, and ER stress-induced apoptosis, discussing how these processes can be manipulated in cancer cells and how new treatment strategies can be developed. Targeting ER stress pathways may represent a promising approach, particularly for chemoresistant tumors.