Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation. Deregulation in ER homeostasis, usually called ER stress, can provoke unfolded protein response (UPR) pathways with an aim to initially restore homeostasis by activating genes involved in protein folding and antioxidative machinery. Over time, however, activated UPR involves a variety of cellular signaling pathways which determine the state and fate of cell in large part (like autophagy, apoptosis, ferroptosis, inflammation, senescence, stemness, and cell cycle, etc.). This review will describe the regulation of UPR from the redox perspective in controlling the cell survival or death, emphasizing the redox modifications of UPR sensors/transducers in the ER.

Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress.

The Protein Disulfide Isomerase Family: from proteostasis to pathogenesis.

Background Tumor cells can die via immunogenic cell death pathway, in which damage-associated molecular pattern molecules (DAMPs) are released from the cells. These molecules activate cells involved in the immune response. Both innate and adaptive immune response can be activated, causing a destruction of the remaining infected cells. Activation of immune response is also an important component of tumor treatment with electrochemotherapy (ECT) and irreversible electroporation (IRE). We thus explored, if and when specific DAMPs are released as a consequence of electroporation in vitro. Materials and methods In this in vitro study, 100 μs long electric pulses were applied to a suspension of Chinese hamster ovary cells. The release of DAMPs - specifically: adenosine triphosphate (ATP), calreticulin, nucleic acids and uric acid was investigated at different time points after exposing the cells to electric pulses of different amplitudes. The release of DAMPs was statistically correlated with cell permeabilization and cell survival, e.g. reversible and irreversible electroporation. Results In general, the release of DAMPs increases with increasing pulse amplitude. Concentration of DAMPs depend on the time interval between exposure of the cells to pulses and the analysis. Concentrations of most DAMPs correlate strongly with cell death. However, we detected no uric acid in the investigated samples. Conclusions Release of DAMPs can serve as a marker for prediction of cell death. Since the stability of certain DAMPs is time dependent, this should be considered when designing protocols for detecting DAMPs after electric pulse treatment.

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

The protein disulphide isomerase (PDI) gene family is a large, diverse group of enzymes recognised for their roles in disulphide bond formation within the endoplasmic reticulum (ER). PDI therefore plays an important role in ER proteostasis, however, it also shows involvement in ER stress, a characteristic recognised in multiple disease states, including cancer. While the exact mechanisms by which PDI contributes to tumorigenesis are still not fully understood, PDI exhibits clear involvement in the unfolded protein response (UPR) pathway. The UPR acts to alleviate ER stress through the activation of ER chaperones, such as PDI, which act to refold misfolded proteins, promoting cell survival. PDI also acts as an upstream regulator of the UPR pathway, through redox regulation of UPR stress receptors. This demonstrates the pro-protective roles of PDI and highlights PDI as a potential therapeutic target for cancer treatment. Recent research has explored the use of PDI inhibitors with PACMA 31 in particular, demonstrating promising anti-cancer effects in ovarian cancer. This review discusses the properties and functions of PDI family members and focuses on their potential as a therapeutic target for cancer treatment.

/pdf/protein-disulphide-isomerase-inhibition-as-a-potential-2bret12dt0.pdf

Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy

Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) that results in transient suppression of protein translation to allow recovery but leads to cell death when stress cannot be resolved. Central to initiation of the UPR is the activation of the ER transmembrane kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Here we report that the thiol oxidoreductase ERp57 and protein disulfide isomerase-A1 (PDI), which belong to the same family of luminal ER oxidoreductases, have strikingly opposing roles in the regulation of PERK function. In HCT116 colon carcinoma cells, lentiviral depletion of ERp57 resulted in oxidation of PDI and activation of PERK, whereas depletion or chemical inhibition of PDI reduced PERK signaling and sensitized the cancer cells to hypoxia and ER stress. We conclude that oxidized PDI acts as a PERK activator, whereas ERp57 keeps PDI in a reduced state in the absence of ER stress. Thus, our study defines a new interface between metabolic redox signaling and PERK-dependent activation of the UPR and has the potential to influence future cancer therapies that target PERK signaling.

/pdf/pdi-is-an-essential-redox-sensitive-activator-of-perk-during-1ck93oops8.pdf

PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR)

The disulfide isomerase ERp57, originally found in the endoplasmic reticulum, is located in multiple cellular compartments, participates in diverse cell functions and interacts with a huge network of binding partners It was recently suggested as an attractive new target for cancer therapy due to its critical role in tumor cell proliferation Since a major bottleneck in cancer treatment is the occurrence of hypoxic areas in solid tumors, the role of ERp57 in cell growth was tested under oxygen depletion in the colorectal cancer cell line HCT116 We observed a severe growth inhibition when ERp57 was knocked down in hypoxia (1% O2) as a consequence of downregulated c-Myc, PLK1, PDPK1 (PDK1) and AKT (PKB) Further, irradiation experiments revealed also a radiosensitizing effect of ERp57 depletion under oxygen deprivation Compared to ERp57, we do not favour PDPK1 as a suitable pharmaceutical target as its efficient knockdown/chemical inhibition did not show an inhibitory effect on proliferation

/pdf/in-oxygen-deprived-tumor-cells-erp57-provides-44rg1yd35d.pdf

Tobias Ocklenburg

Papers

PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR)

In oxygen-deprived tumor cells ERp57 provides radioprotection and ensures proliferation via c-Myc, PLK1 and the AKT pathway