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Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 44700

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Special Issue Editors

Dr. Ivan Poon

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Guest Editor

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
Interests: cell death; apoptosis; apoptotic bodies; extracellular vesicles; cell clearance; efferocytosis

Dr. Georgia Atkin-Smith

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Co-Guest Editor

La Trobe University, Melbourne, Australia
Interests: apoptosis; infectious disease; cancer; cell clearance; apoptotic bodies
Special Issues, Collections and Topics in MDPI journals

Dr. Rochelle Tixeira

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Co-Guest Editor

Vlaams Institute for Biotechnology, Ghent, Belgium
Interests: apoptosis; secondary necrosis; extracellular vesicles; inflammation; cell clearance; reproductive biology

Dr. Amy A. Baxter

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Co-Guest Editor

La Trobe Institute for Molecular Science, Dept Biochemistry & Genetics, La Trobe University, Melbourne, VIC, Australia
Interests: extracellular vesicles; cell death; apoptosis; apoptotic bodies; inflammation; atherosclerosis; cell clearance

Special Issue Information

Dear Colleagues,

Cell death plays a crucial role in maintaining homeostasis through the elimination of excessive, infected, malignant and damaged cells. Over the past decade, the field of cell death has been evolving at a rapid pace with the identification of novel mechanisms underpinning the complex molecular control of cell death. In addition to the classically studied mechanisms of intrinsic and extrinsic apoptosis, new forms of Programmed Cell Death (PCD) are being uncovered. PCD is defined by a controlled signal pathway which results in cellular demise through apoptosis, necroptosis or pyroptosis. Notably, cell death is not always executed in an organised fashion, as seen in primary necrotic and secondary necrotic cell death. Furthermore, the mechanism of cell death can be cell-type specific as seen in NETosis (a specialized form of PCD occurring in neutrophils), driven through specific organelles (lysosomal cell death) and cellular processes (autophagic cell death). Moreover, the cell death field continues to expand with research characterizing novel cell death pathways such as ferroptosis, linker cell death, and parthanatos.

It is important to decipher the complex and overlapping molecular control of dying cells, as defects in the cell death pathway has been linked to a variety of diseases such as cancer and inflammation. Importantly, understanding the molecular mechanisms of cell death and its impairment in many cancer types has led to the development of novel anti-cancer therapeutics. Moreover, many inflammatory disorders, including autoimmunity, asthma, inflammatory bowel disease and transplant rejections, can be a result of enhanced inflammatory cell death. Thus, it is imperative to dissect the relationship between cell death and disease in order to develop much needed therapeutics.

For this Special Issue of Biomolecules, “Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment”, we encourage the submission of review and primary research articles that showcase both the role of cell death and therapeutic approaches targeting cell death pathways in cancer and inflammation.

Dr. Ivan Poon
Guest Editor
Dr. Georgia Atkin-Smith
Dr. Rochelle Tixeira
Dr. Amy A. Baxter
Co-Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cell death
apoptosis
necroptosis
pyroptosis
cancer
inflammation

Published Papers (9 papers)

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Research

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18 pages, 3851 KiB

Open AccessFeature PaperArticle

Reconstitution of Human Necrosome Interactions in Saccharomyces cerevisiae

by Y. Ji, L. A. Ward and C. J. Hawkins

Biomolecules 2021, 11(2), 153; https://doi.org/10.3390/biom11020153 - 25 Jan 2021

Cited by 3 | Viewed by 2327

Abstract

The necrosome is a large-molecular-weight complex in which the terminal effector of the necroptotic pathway, Mixed Lineage Kinase Domain-Like protein (MLKL), is activated to induce necroptotic cell death. The precise mechanism of MLKL activation by the upstream kinase, Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) and the role of Receptor Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in mediating MLKL activation remain incompletely understood. Here, we reconstituted human necrosome interactions in yeast by inducible expression of these necrosome effectors. Functional interactions were reflected by the detection of phosphorylated MLKL, plasma membrane permeabilization, and reduced proliferative potential. Following overexpression of human necrosome effectors in yeast, MLKL aggregated in the periphery of the cell, permeabilized the plasma membrane and compromised clonogenic potential. RIPK1 had little impact on RIPK3/MLKL-mediated yeast lethality; however, it exacerbated the toxicity provoked by co-expression of MLKL with a RIPK3 variant bearing a mutated RHIM-domain. Small molecule necroptotic inhibitors necrostatin-1 and TC13172, and viral inhibitors M45 (residues 1–90) and BAV_Rmil, abated the yeast toxicity triggered by the reconstituted necrosome. This yeast model provides a convenient tool to study necrosome protein interactions and to screen for and characterize potential necroptotic inhibitors. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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17 pages, 4404 KiB

Open AccessArticle

Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner

by Pei-Ming Yang, Yao-Yu Hsieh, Jia-Ling Du, Shih-Chieh Yen and Chien-Fu Hung

Biomolecules 2020, 10(4), 643; https://doi.org/10.3390/biom10040643 - 21 Apr 2020

Cited by 20 | Viewed by 3248

Abstract

Immunogenic cell death (ICD) refers to a unique form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Accumulating evidence indicates that the efficacy of conventional anticancer agents relies on not only their direct cytostatic/cytotoxic effects but also the activation of antitumor ICD. Common anticancer ICD inducers include certain chemotherapeutic agents (such as anthracyclines, oxaliplatin, and bortezomib), radiotherapy, photodynamic therapy (PDT), and oncolytic virotherapies. However, most chemotherapeutic reagents are inefficient or fail to trigger ICD. Therefore, better understanding on the molecular determinants of chemotherapy-induced ICD will help in the development of more efficient combinational anticancer strategies through converting non- or relatively weak ICD inducers into bona fide ICD inducers. In this study, we found that sequential, but not concurrent, treatment of cancer cells with interferon β (IFNβ), a type I IFN, and cisplatin (an inefficient ICD inducer) can enhance the expression of ICD biomarkers in cancer cells, including surface translocation of an endoplasmic reticulum (ER) chaperone, calreticulin (CRT), and phosphorylation of the eukaryotic translation initiation factor alpha (eIF2α). These results suggest that exogenous IFNβ may activate molecular determinants that convert cisplatin into an ICD inducer. Further bioinformatics and in vitro experimental analyses found that interferon regulatory factor 1 (IRF1) acted as an essential mediator of surface CRT exposure by sequential IFNβ-cisplatin combination. Our findings not only help to design more effective combinational anticancer therapy using IFNβ and cisplatin, but also provide a novel insight into the role of IRF1 in connecting the type I IFN responses and ICD. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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15 pages, 1979 KiB

Open AccessArticle

BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response

by Janakiram R. Vangala, Ajay Potluri and Senthil K. Radhakrishnan

Biomolecules 2020, 10(4), 501; https://doi.org/10.3390/biom10040501 - 26 Mar 2020

Cited by 14 | Viewed by 3133

Abstract

Currently, proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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12 pages, 2375 KiB

Open AccessArticle

UFL1 Alleviates LPS-Induced Apoptosis by Regulating the NF-κB Signaling Pathway in Bovine Ovarian Granulosa Cells

by Xinling Wang, Chengmin Li, Yiru Wang, Lian Li, Zhaoyu Han and Genlin Wang

Biomolecules 2020, 10(2), 260; https://doi.org/10.3390/biom10020260 - 09 Feb 2020

Cited by 21 | Viewed by 3712

Abstract

Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) is an E3 ligase of ubiquitin fold modifier 1 (UFM1), which can act together with its target protein to inhibit the apoptosis of cells. Lipopolysaccharides (LPS) can affect the ovarian health of female animals by affecting the apoptosis of ovarian granulosa cells. The physiological function of UFL1 on the apoptosis of bovine (ovarian) granulosa cells (bGCs) remains unclear; therefore, we focused on the modulating effect of UFL1 on the regulation of LPS-induced apoptosis in ovarian granulosa cells. Our study found that UFL1 was expressed in both the nucleus and cytoplasm of bGCs. The results here demonstrated that LPS caused a significant increase in the apoptosis level of bGCs in cows, and also dramatically increased the expression of UFL1. Furthermore, we found that UFL1 depletion caused a significant increase in apoptosis (increased the expression of BAX/BCL-2 and the activity of caspase-3). Conversely, the overexpression of UFL1 relieved the LPS-induced apoptosis. In order to assess whether the inhibition of bGCs apoptosis involved in the nuclear factor-κB (NF-κB) signaling pathway resulted from UFL1, we detected the expression of NF-κB p-p65. LPS treatment resulted in a significant upregulation in the protein concentration of NF-κB p-p65, and knockdown of UFL1 further increased the phosphorylation of NF-κB p65, while UFL1 overexpression significantly inhibited the expression of NF-κB p-p65. Collectively, UFL1 could suppress LPS-induced apoptosis in cow ovarian granulosa cells, likely via the NF-κB pathway. These results identify a novel role of UFL1 in the modulation of bGC apoptosis, which may be a potential signaling target to improve the reproductive health of dairy cows. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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Review

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15 pages, 1199 KiB

Open AccessReview

Inflammation and Cell Death of the Innate and Adaptive Immune System during Sepsis

by Christina Nedeva

Biomolecules 2021, 11(7), 1011; https://doi.org/10.3390/biom11071011 - 10 Jul 2021

Cited by 62 | Viewed by 9559

Abstract

Sepsis is a life-threatening medical condition that occurs when the host has an uncontrolled or abnormal immune response to overwhelming infection. It is now widely accepted that sepsis occurs in two concurrent phases, which consist of an initial immune activation phase followed by a chronic immunosuppressive phase, leading to immune cell death. Depending on the severity of the disease and the pathogen involved, the hosts immune system may not fully recover, leading to ongoing complications proceeding the initial infection. As such, sepsis remains one of the leading causes of morbidity and mortality world-wide, with treatment options limited to general treatment in intensive care units (ICU). Lack of specific treatments available for sepsis is mostly due to our limited knowledge of the immuno-physiology associated with the disease. This review will provide a comprehensive overview of the mechanisms and cell types involved in eliciting infection-induced immune activation from both the innate and adaptive immune system during sepsis. In addition, the mechanisms leading to immune cell death following hyperactivation of immune cells will be explored. The evaluation and better understanding of the cellular and systemic responses leading to disease onset could eventuate into the development of much needed therapies to combat this unrelenting disease. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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22 pages, 921 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

by Emma C. Tovey Crutchfield, Sarah E. Garnish and Joanne M. Hildebrand

Biomolecules 2021, 11(6), 803; https://doi.org/10.3390/biom11060803 - 28 May 2021

Cited by 14 | Viewed by 3663

Abstract

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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15 pages, 1834 KiB

Open AccessFeature PaperReview

Cardiac Glycosides as Immune System Modulators

by Jan Škubník, Vladimíra Pavlíčková and Silvie Rimpelová

Biomolecules 2021, 11(5), 659; https://doi.org/10.3390/biom11050659 - 29 Apr 2021

Cited by 25 | Viewed by 7537

Abstract

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na⁺/K⁺-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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22 pages, 1312 KiB

Open AccessReview

Targeting RIP Kinases in Chronic Inflammatory Disease

by Mary Speir, Tirta M. Djajawi, Stephanie A. Conos, Hazel Tye and Kate E. Lawlor

Biomolecules 2021, 11(5), 646; https://doi.org/10.3390/biom11050646 - 28 Apr 2021

Cited by 19 | Viewed by 5214

Abstract

Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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20 pages, 1664 KiB

Open AccessReview

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

by Anna Negroni, Eleonora Colantoni, Salvatore Cucchiara and Laura Stronati

Biomolecules 2020, 10(10), 1431; https://doi.org/10.3390/biom10101431 - 10 Oct 2020

Cited by 31 | Viewed by 5032

Abstract

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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