bims-ershed 2021-08-22 papers

Biochem Pharmacol. 2021 Aug 16. pii: S0006-2952(21)00353-1. [Epub ahead of print] 114737

The unfolded protein response as regulator of cancer stemness and differentiation: mechanisms and implications for cancer therapy.

Dong Liang, Mohammad Khoonkari, Tony Avril, Eric Chevet, Frank A E Kruyt.

The unfolded protein response (UPR) is an adaptive mechanism that regulates protein and cellular homeostasis. Three endoplasmic reticulum (ER) membrane localized stress sensors, IRE1, PERK and ATF6, coordinate the UPR in order to maintain ER proteostasis and cell survival, or induce cell death when homeostasis cannot be restored. However, recent studies have identified alternative functions for the UPR in developmental biology processes and cell fate decisions under both normal and cancerous conditions. In cancer, increasing evidence points towards the involvement of the three UPR sensors in oncogenic reprogramming and the regulation of tumor cells endowed with stem cell properties, named cancer stem cells (CSCs), that are considered to be the most malignant cells in tumors. Here we review the reported roles and underlying molecular mechanisms of the three UPR sensors in regulating stemness and differentiation, particularly in solid tumor cells, processes that have a major impact on tumor aggressiveness. Mainly PERK and IRE1 branches of the UPR were found to regulate CSCs and tumor development and examples are provided for breast cancer, colon cancer and aggressive brain tumors, glioblastoma. Although the underlying mechanisms and interactions between the different UPR branches in regulating stemness in cancer need to be further elucidated, we propose that PERK and IRE1 targeted therapy could inhibit self-renewal of CSCs or induce differentiation that is predicted to have therapeutic benefit. For this, more specific UPR modulators need to be developed with favorable pharmacological properties that together with patient stratification will allow optimal evaluation in clinical studies.

Keywords: IRE1; PERK; cancer stem cells; therapy; tumor formation; unfolded protein response

DOI: https://doi.org/10.1016/j.bcp.2021.114737

Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00025-3. [Epub ahead of print]363 1-20

Calcium signaling and endoplasmic reticulum stress.

Jody Groenendyk, Luis B Agellon, Marek Michalak.

Cellular homeostasis is essential for healthy functioning of cells and tissues as well as proper organ development and maintenance. A disruption in cellular homeostasis triggers stress responses including the unfolded protein response (UPR), an endoplasmic reticulum (ER) stress coping response. There is increasing evidence that Ca2+ signaling plays a pivotal role in stress responses, as Ca2+ is involved many cellular activities. The ER is the main Ca2+ storage organelle and the source of Ca2+ for intracellular signaling. The ER is equipped with a variety of stress sensors and contains many Ca2+ handling proteins that support a role for Ca2+ in stress sensing and in coordinating strategies required to cope with cellular stress. Maintenance of ER Ca2+ homeostasis is therefore vital in sustaining cellular functions especially during times of cellular stress. Here we focus on selected aspects of ER Ca2+ homeostasis, its links to ER stress, and activation of the ER stress coping response.

Keywords: Chaperones; Endoplasmic reticulum; Membrane contact site; Ryanodine receptor; Sarcoplasmic reticulum; Unfolded protein response

DOI: https://doi.org/10.1016/bs.ircmb.2021.03.003

Int J Neurosci. 2021 Aug 17. 1-32

Protein misfolding, ER Stress and Chaperones: An approach to develop chaperone-based therapeutics for Alzheimer's Disease.

Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder with complex etiology that eventually leads to dementia. The main culprit of AD is the extracellular deposition of β-amyloid (Aβ) and intracellular neurofibrillary tangles. The protein conformational change and protein misfolding are the key events of AD pathophysiology, therefore endoplasmic reticulum (ER) stress is an apparent consequence. ER, stress-induced unfolded protein response (UPR) mediators (viz. PERK, IRE1, and ATF6) have been reported widely in the AD brain. Considering these factors, preventing proteins misfolding or aggregation of tau or amyloidogenic proteins appears to be the best approach to halt its pathogenesis. Therefore, therapies through chemical and pharmacological chaperones came to light as an alternative for the treatment of AD. Diverse studies have demonstrated 4-phenylbutyric acid (4-PBA) as a potential therapeutic agent in AD. The current review outlined the mechanism of protein misfolding, different etiological features behind the progression of AD, the significance of ER stress in AD, and the potential therapeutic role of different chaperones to counter AD. The study also highlights the gaps in current knowledge of the chaperones-based therapeutic approach and the possibility of developing chaperones as a potential therapeutic agent for AD treatment.

Keywords: Alzheimer’s disease; chemical chaperone; unfolded protein response; β-amyloid

DOI: https://doi.org/10.1080/00207454.2021.1968859

Haematologica. 2021 Aug 19.

Therapeutic targeting of endoplasmic reticulum stress in acute graft-versus-host disease.

Eileen Haring, Geoffroy Andrieux, Franziska M Uhl, Máté Krausz, Michele Proietti, Barbara Sauer, Philipp R Esser, Stefan F Martin, Dietmar Pfeifer, Annette Schmitt-Graeff, Justus Duyster, Natalie Köhler, Bodo Grimbacher, Melanie Boerries, Konrad Aumann, Robert Zeiser, Petya Apostolova.

Acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GVHD and can be targeted pharmacologically. We observed high levels of ER stress upon GVHD onset in a murine allo-HCT model and in human biopsies. These levels correlated with GVHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GVHD lethality. This phenotype was mediated by changes in the production of anti-microbial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1 alpha (IRE1α), the most conserved signaling branch in ER stress, reduced GVHD development in mice. IRE1α blockade by the small molecule inhibitor 4µ8c improved intestinal cell viability, without impairing hematopoietic regeneration and T cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GVHD. Reducing ER stress could improve the outcome of patients suffering from GVHD.

DOI: https://doi.org/10.3324/haematol.2021.278387

ACS Nano. 2021 Aug 20.

Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy.

Mengshi Jiang, Xiang Li, Junlei Zhang, Yichao Lu, Yingying Shi, Chunqi Zhu, Yu Liu, Bing Qin, Zhenyu Luo, Yongzhong Du, Lihua Luo, Ling Peng, Jian You.

M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.

Keywords: ER stress; anti-PD-1 immunotherapy; hypoxia; macrophages repolarization; oxidative stress

DOI: https://doi.org/10.1021/acsnano.1c04068