ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

Abstract

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

“…Therefore, its increase in cellular levels is related to both cell survival and death, as its transcription is amplified in an attempt to normalize protein synthesis, prevented by the PERK pathway. The reversal of the inhibition of the translation process leads not only to the production of apoptotic proteins, but also to those related to cell continuity (Ma and Hendershot, 2003;Adams et al, 2019;Féral et al, 2021). The activation of this pathway reinforces the importance of proteasome inhibitors as an interesting option for cancer therapy.…”

Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2α, and HIF-1α

“…Accordingly, eIF-2α hyperphosphorylation in response to environmental stress or drug exposure reduces global translation [ 37 ]. Of note, previous studies have demonstrated the CX-4945-induced eIF-2α hyperphosphorylation in eye cells [ 38 ] and leukemia cells [ 39 ]. In agreement with this, we have shown the capability of CX-4945 to elevate the phosphorylation of eIF-2α in HuCCT-1 cells.…”

Circular RNAs Activity in the Leukemic Bone Marrow Microenvironment

“…These vesicles transfer different bioactive molecules such as proteins, lipids, DNA and RNA. Since hypoxia, nutrients deprivation and acidosis render bone marrow an extremely hostile environment even for leukemic blasts, they cope with ER stress conditions by activating the unfolded protein response (UPR) [ 53 ] and it was shown that AML extracellular vesicles (AML-EVs) transfer ER stress to bone marrow mesenchymal stem cells, thus creating a leukemia permissive microenvironment [ 54 ]. Ultimately, the anchorage of leukemic stem cells to the niche also plays an essential role in AML pathogenesis [ 55 , 56 ].…”