Integrating proteotoxic stress response pathways for induction of cell death in cancer cells: Molecular mechanisms and therapeutic opportunities

The endoplasmic reticulum (ER) is a major organelle that is involved in protein synthesis, and in proper maintenance of cellular homeostasis and adaptation to adverse environments. Perturbations in the cellular environment is sensed by transmembrane ER resident proteins to initiate an intricate and highly conserved signal transduction pathway called the unfolded protein response (UPR). The central objective of the UPR is to prevent the accumulation of unfolded/misfolded proteins in the UPR and adapt to cellular stress by promoting cell survival. However, if a threshold is exceeded by the stress, the UPR can trigger programmed cell death pathways. The ability of the UPR to maintain survival has important implication in human diseases such as cancer. Cancer cells can up-regulate signaling associated with the UPR to promote growth and resist anti-cancer therapy. Knowledge of the mechanism associated with the UPR may provide novel therapeutic targets for cancer therapy.