Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling

Spaan, Claudia N.; Smit, Wouter L.; Jeude, Jooske F. van Lidth de; Meijer, Bartolomeus J.; Muncan, Vanesa; Brink, Gijs R. van den; Heijmans, Jarom

doi:10.1038/s41419-019-1729-4

Cited by 94 publications

(76 citation statements)

References 53 publications

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“…In the intestine, activation of UPR by PERK kinase leads to differentiation of intestinal epithelial stem cells and colon CSCs, and the absence of X box binding protein 1 results in increased stemness and adenoma formation. X box binding protein 1 activation results in reduced cell proliferation and intestinal epithelial cell stemness due to cross-activation of the PERK-eIF2α signaling[ 150 ]. In pancreatic cancer, GRP78 downregulates stem cell clone formation and self-renewal characteristics, suggesting that the UPR plays a role in inhibiting stemness in pancreatic cancer[ 151 ].…”

Section: Impact Of Ros From Pdt On Cscsmentioning

confidence: 99%

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

Zhang

Wang

et al. 2020

WJSC

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Photodynamic therapy (PDT) is an effective and promising cancer treatment. PDT directly generates reactive oxygen species (ROS) through photochemical reactions. This oxygen-dependent exogenous ROS has anti-cancer stem cell (CSC) effect. In addition, PDT may also increase ROS production by altering metabolism, endoplasmic reticulum stress, or potential of mitochondrial membrane. It is known that the half-life of ROS in PDT is short, with high reactivity and limited diffusion distance. Therefore, the main targeting position of PDT is often the subcellular localization of photosensitizers, which is helpful for us to explain how PDT affects CSC characteristics, including differentiation, self-renewal, apoptosis, autophagy, and immunogenicity. Broadly speaking, excess ROS will damage the redox system and cause oxidative damage to molecules such as DNA, change mitochondrial permeability, activate unfolded protein response, autophagy, and CSC resting state. Therefore, understanding the molecular mechanism by which ROS affect CSCs is beneficial to improve the efficiency of PDT and prevent tumor recurrence and metastasis. In this article, we review the effects of two types of photochemical reactions on PDT, the metabolic processes, and the biological effects of ROS in different subcellular locations on CSCs.

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Section: Impact Of Ros From Pdt On Cscsmentioning

confidence: 99%

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

Zhang

Wang

et al. 2020

WJSC

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“…GADD34 is responsible for dephosphorylating eIF2α and reinstating protein translation after correcting misfolded proteins (Kroemer et al, 2010). Therefore, the aggregation of stem cells may result in a new protein homeostatic state, with lower level of GADD34 shown in our study (Kratochvilova et al, 2016;Spaan et al, 2019;Young, Palam, Wu, Sachs, & Wek, 2016). CHOP generally follows the changes of its upstream regulator, ATF4 to activate autophagy under stress response (B'Chir et al, 2013).…”

Section: Proteomics Analysis Reveals the Role Of Isr In Msc Homeostmentioning

confidence: 58%

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Bijonowski

Yuan

et al. 2020

Biotech & Bioengineering

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Protein homeostasis is critical for cellular function, as loss of homeostasis is attributed to aging and the accumulation of unwanted proteins. Human mesenchymal stem cells (MSCs) have shown promising therapeutic potential due to their impressive abilities to secrete inflammatory modulators, angiogenic, and regenerative cytokines. However, there exists the problem of human MSC expansion with compromised therapeutic quality. Duringin vitro expansion, human MSCs are plated on stiff plastics and undergo culture adaptation, which results in aberrant proliferation, shifts in metabolism, and decreased autophagic activity. It has previously been shown that three‐dimensional (3D) aggregation can reverse some of these alterations by heightening autophagy and recovering the metabolic state back to a naïve phenotype. To further understand the proteostasis in human MSC culture, this study investigated the effects of 3D aggregation on the human MSC proteome to determine the specific pathways altered by aggregation. The 3D aggregates and 2D cultures of human MSCs derived from bone marrow (bMSC) and adipose tissue (ASC) were analyzed along with differentiated human dermal fibroblasts (FB). The proteomics analysis showed the elevated eukaryotic initiation factor 2 pathway and the upregulated activity of the integrated stress response (ISR) in 3D aggregates. Specific protein quantification further determined that bMSC and ASC responded to ISR, while FB did not. 3D aggregation significantly increased the ischemic survival of bMSCs and ASCs. Perturbation of ISR with small molecules salubrinal and GSK2606414 resulted in differential responses of bMSC, ASC, and FB. This study indicates that aggregation‐based preconditioning culture holds the potential for improving the therapeutic efficacy of expanded human MSCs via the establishment of ISR and homeostasis.

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“…Interestingly, a high level of ATF6 has been strictly correlated with cancer metastasis and recurrence [187]. In a CRC model, the activation of XBP1 and ATF6 resulted in reduction of stemness and proliferation of cancer cells via the crossactivation of the PERK-eIF2α signaling pathway [188]. On the contrary, higher expression of ATF6 was found in lesions undergoing pre-cancerous atypical change in CRC [189], as well as it was correlated with poor prognosis in patients suffering from CRC [190,191].…”

Section: Molecular Basis Of Upr In Cancer Developmentmentioning

confidence: 99%

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

Siwecka

Rozpędek

Pytel

et al. 2019

IJMS

116

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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.

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Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling

Cited by 94 publications

References 53 publications

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

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