The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

Abstract

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Malignant diseases are characterized by the development of abnormal cells that are capable of dividing uncontrollably and infiltrate and destroy normal body tissue. In the context of quickly proliferating cells, an enhanced demand for protein synthesis exists, thus ER is a key organelle guarding proper cellular functioning in cancer [84,172]. In terms of oncotherapy, the role of the UPR signaling in malignant cells may be controversial, since the pro-survival branch of the UPR aims at rescuing transformed cells.…”

Unfolded protein response regulates P53 expression in the pulmonary endothelium

“…DTT is a strong reducing agent and blocks disulfide‐bond formation. TG is noncompetitive inhibitor of the sarco/endoplasmic reticulum Ca 2+ ATPase . All three inducers, increased P53 expression levels.…”

“…To the best of our knowledge, the present study is the first to report that the modulation of the UPR activation by a variety of chemical UPR inducers and suppressors regulate the expression of P53 in bovine endothelial cells. It is well documented that a severe induction of both UPR and P53 triggers apoptotic effects . However, various independent research groups support an alternative approach.…”

Energy Restriction and Colorectal Cancer: A Call for Additional Research

“…Importantly, excessive ROS surpassing the antioxidant capacity threshold may result in severe ERS, unsustainable macromolecular damage, and cellular death [146,148]. In fact, increased susceptibility to ROSand ERS-inducing cell death is documented for cancer cells, representing a window for multiple ROS-and ERS-driven anti-cancer therapies oriented to either increase the rate of OXPHOS or ROS production [149], ERS induction [150,151], or to inhibit ROS scavenging [149]. In the context of CRC, Rubio-Patiño and colleagues showed in different mouse cancers models of CRC that mice fed a low-protein diet prompted the induction of IRE1α and RIG1 signaling downstream of ERS, resulting in increased levels of cytokines, effective assembly of the immune response, and reduced colorectal tumor growth [146].…”