Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities

Khateb, Ali; Ronai, Ze’ev

doi:10.1016/j.trecan.2020.05.012

Cited by 24 publications

(36 citation statements)

References 118 publications

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“…At steady state, HSCs are quiescent and display lower protein synthesis rates in vivo and in vitro compared to their progeny [ 136 ]. Furthermore, HSCs have been associated with low protein folding capacity that can be explained by a lower expression of chaperones proteins compared to hematopoietic progenitors [ 137 ]. Moreover, protein synthesis deregulation has a great impact on HSCs’ viability and self-renewal capacities and can lead to HSCs loss [ 136 , 138 ].…”

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

“…Indeed, hematopoietic cells, either normal or leukemic, are exposed in the bone marrow to an adverse environment caused by hypoxia, high levels of reactive oxygen species (ROS), and nutrient deprivation, often resulting in ER stress activation [ 13 , 16 , 23 , 148 ]. Thus, many studies have reported the activation, to variable extents, of each of the three UPR branches (IRE1α, PERK, and ATF6α) in a wide range of hematopoietic tumors (leukemia, lymphoma, and myeloma) [ 137 , 149 , 150 , 151 ]. As in solid cancers, UPR plays a fundamental role in the adaptation of leukemic cells to cellular stress by inducing different mechanisms, which attempt to reestablish ER homeostasis in order to restore its proper functions.…”

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

“…By analogy with what is observed in HSCs under normal growth conditions, the UPR response may represent a real checkpoint influencing cell fate of leukemic cells experiencing chemotherapy: either the stress can be resolved via an adaptive phase and cancer progresses or the damage accumulates and becomes unrecoverable. In this latter case, excessive or prolonged stress triggers proapoptotic signaling through a terminal process [ 137 , 150 , 151 , 160 ]. This important issue is discussed below.…”

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

“…Altogether, the data presented above have largely validated the inhibition of adaptive UPR as an effective means of fighting leukemia and a significant number of pharmacological inhibitors of central UPR effectors are currently under preclinical studies or clinical trials [ 137 , 150 ].…”

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

“…In this latter case, excessive or prolonged stress triggers proapoptotic signaling through a terminal process [137,150,151,160]. This important issue is discussed below.…”

Section: Er Stress Activation In Leukemic Cellsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress Induction In Hematopoietic Amentioning

confidence: 99%

“…In this latter case, excessive or prolonged stress triggers proapoptotic signaling through a terminal process [137,150,151,160]. This important issue is discussed below.…”

Section: Er Stress Activation In Leukemic Cellsmentioning

confidence: 99%

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

et al. 2021

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Emerging role of IRE1α in vascular diseases

Shi,

He,

2024

Journal of Cell Communication and Signaling

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A mounting body of evidence suggests that the endoplasmic reticulum stress and the unfolded protein response are involved in the underlying mechanisms responsible for vascular diseases. Inositol‐requiring protein 1α (IRE1α), the most ancient branch among the UPR‐related signaling pathways, can possess both serine/threonine kinase and endoribonuclease (RNase) activity and can perform physiological and pathological functions. The IRE1α‐signaling pathway plays a critical role in the pathology of various vascular diseases. In this review, we provide a general overview of the physiological function of IRE1α and its pathophysiological role in vascular diseases.

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