Abstract
Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy.
Highlights
In this day and age, cancer and other types of neoplastic growths have become a global health problem, since many of them bear hallmarks of rapid progression and poor prognosis [1,2]
Research by Rojas-Rivera et al [286] has demonstrated that both GSK2606414 and GSK2656157, commonly used as inhibitors of the PERK-dependent Unfolded Protein Response (UPR) signaling pathway, trigger complete inhibition of the tumor necrosis factor (TNF)-mediated receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent cell death in the nanomolar range and the above-mentioned inhibitory effect was independent of PERK inactivation
Since UPR is capable of triggering both pro-survival and pro-apoptotic signals, it is still unclear whether the protective elements of the response are enhanced or the destructive ones suppressed in order to prevent the UPR-induced apoptosis [132]
Summary
In this day and age, cancer and other types of neoplastic growths have become a global health problem, since many of them bear hallmarks of rapid progression and poor prognosis [1,2]. Chemotherapy is currently considered imperfect and non-specific, associated with long-term, irreversible side-effects [8,9,10,11], which in the worst-case scenario may increase the risk of development of another types of cancer later on in patients’ life [12]. Its low solubility makes it difficult to applicate in vivo. Another antineoplastic, alkylating agent, Cyclophosphamide (CPA), mostly used along with cancer treatment in bone marrow transplantation and certain autoimmune disorders, has proved to be highly toxic for the targeted cancer cells, and for normal cells of the human body [16,17]. Further research in the field of signaling pathways to discover novel, anti-cancer drugs and thereby improve currently used treatment strategies and minimize their side-effects, has clearly become necessary
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