Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini, Claudio; Iuliano, Luca

doi:10.3390/cancers12092385

Cited by 46 publications

(31 citation statements)

References 227 publications

(269 reference statements)

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“…Proteins with hydrophobic residues and complex 3-dimensional structures require molecular chaperones to acquire their functional forms. Numerous co-chaperones further improve the specificity and selectivity of the process ( 1 , 2 ). In stress conditions, the survival of cells depends on the activation of an elaborate cytoprotective mechanism known as the heat-shock response (HSR).…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Proteins and HSF1 in Cancer

Cyran

Zhitkovich

2022

Front. Oncol.

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Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones – the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence (“addiction”) on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.

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Section: Introductionmentioning

confidence: 99%

Heat Shock Proteins and HSF1 in Cancer

Cyran

Zhitkovich

2022

Front. Oncol.

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“…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%

“…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%

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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“…The classic heat shock response is orchestrated by transcription factor HSF1, which elevates the production of chaperones that facilitate the refolding or recycling of affected molecules [ 23 ]. Furthermore, the accumulation of misfolded proteins in the endoplasmic reticulum (“ER stress”) triggers a specialized and complex unfolded protein response through PERK, IRE1α, and ATF6 [ 24 , 25 ]. Activation of these sensors collectively attenuates the general biosynthesis of new proteins while facilitating ER-associated protein degradation and the production of factors that promote polypeptide refolding.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, a cell has a limited capacity to deal with proteotoxic stress. When this capacity is overwhelmed, the pro-survival cellular program converts into a program of cell death [ 24 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Babagana

Brown

Slabodkin

et al. 2021

IJMS

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Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.

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Proteotoxic Stress and Cell Death in Cancer Cells

Cited by 46 publications

References 227 publications

Heat Shock Proteins and HSF1 in Cancer

Heat Shock Proteins and HSF1 in Cancer

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

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

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