scholarly journals Ferroptosis in Cancer Cell Biology

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 164 ◽  
Author(s):  
Christina M. Bebber ◽  
Fabienne Müller ◽  
Laura Prieto Clemente ◽  
Josephine Weber ◽  
Silvia von Karstedt
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Potential Role ◽  
Kinase Activity ◽  
Systemic Treatment ◽  
Interacting Protein ◽  
Tumour Immunology ◽  
Tumour Suppression ◽  
Regulated Necrosis ◽  
Review Current

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

scholarly journals Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding

2018 ◽  
Vol 26 (3) ◽  
pp. 503-513 ◽  
Author(s):  
Sanae Haga ◽  
Akira Kanno ◽  
Takeaki Ozawa ◽  
Naoki Morita ◽  
Mami Asano ◽  
...  
Keyword(s):  
Cell Death ◽  
Specific Inhibitor ◽  
Apoptotic Pathway ◽  
Interacting Protein ◽  
Cellular Processes ◽  
Hepatocyte Injury ◽  
Caspase Inhibition ◽  
Regulated Necrosis ◽  
Tnf Α ◽  
Optic Probe

Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1 (RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-α/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H2O2, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H2O2, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis.

scholarly journals NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation

2021 ◽  
Vol 4 (6) ◽  
pp. e202000956
Author(s):  
Snehlata Kumari ◽  
Trieu-My Van ◽  
Daniela Preukschat ◽  
Hannah Schuenke ◽  
Marijana Basic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Tumor Necrosis ◽  
Kinase Activity ◽  
Tumor Necrosis Factor Receptor ◽  
Skin Inflammation ◽  
Interacting Protein ◽  
Inflammatory Gene Expression ◽  
Underlying Mechanisms ◽  
Necrosis Factor

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB–dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)–dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB–dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.

scholarly journals The Receptor Interacting Protein Kinases in the Liver

2018 ◽  
Vol 38 (01) ◽  
pp. 073-086 ◽  
Author(s):  
Lily Dara
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Kinase Activity ◽  
Cultured Cells ◽  
Interacting Protein ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Cell Death Signaling ◽  
Experimental Liver ◽  
Mediate Inflammation

AbstractThe receptor interacting serine/threonine kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the mixed lineage domain like pseudokinase. Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis-independent role warrants further examination.

scholarly journals Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Raul Chavez-Valdez ◽  
Lee J. Martin ◽  
Frances J. Northington
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Significant Proportion ◽  
Developing Brain ◽  
Neonatal Brain ◽  
Programmed Necrosis ◽  
Interacting Protein ◽  
Neonatal Brain Injury ◽  
Regulated Necrosis

Despite the introduction of therapeutic hypothermia, neonatal hypoxic ischemic (HI) brain injury remains a common cause of developmental disability. Development of rational adjuvant therapies to hypothermia requires understanding of the pathways of cell death and survival modulated by HI. The conceptualization of the apoptosis-necrosis “continuum” in neonatal brain injury predicts mechanistic interactions between cell death and hydrid forms of cell death such as programmed or regulated necrosis. Many of the components of the signaling pathway regulating programmed necrosis have been studied previously in models of neonatal HI. In some of these investigations, they participate as part of the apoptotic pathways demonstrating clear overlap of programmed death pathways. Receptor interacting protein (RIP)-1 is at the crossroads between types of cellular death and survival and RIP-1 kinase activity triggers formation of the necrosome (in complex with RIP-3) leading to programmed necrosis. Neuroprotection afforded by the blockade of RIP-1 kinase following neonatal HI suggests a role for programmed necrosis in the HI injury to the developing brain. Here, we briefly review the state of the knowledge about the mechanisms behind programmed necrosis in neonatal brain injury recognizing that a significant proportion of these data derive from experiments in cultured cell and some from in vivo adult animal models. There are still more questions than answers, yet the fascinating new perspectives provided by the understanding of programmed necrosis in the developing brain may lay the foundation for new therapies for neonatal HI.

scholarly journals The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Christa Park ◽  
Kazuha Koyama ◽  
Sakthi Balaji ◽  
Kohei Kita ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
Survival Function ◽  
Neutrophil Infiltration ◽  
Immune Homeostasis ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Hematopoietic Stem ◽  
Bowel Diseases ◽  
Promote Cell Survival

AbstractReceptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and a perinatal lethality in Ripk1−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil infiltration. In addition, these mice were highly resistant to injury-induced colitis. The increased neutrophil infiltration in the colon and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in protecting colonic DCs from apoptotic insults and maintenance of colonic immune homeostasis.

scholarly journals RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

2020 ◽  
Author(s):  
Liang Tao ◽  
Yuguo Yi ◽  
Yuxin Chen ◽  
Haibing Zhang ◽  
Jiapeng Jie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Disease Progression ◽  
Kinase Activity ◽  
Inflammasome Activation ◽  
Deficient Diet ◽  
Interacting Protein ◽  
Sirius Red

AbstractHepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of α-SMA and other fibrosis markers, were significantly alleviated in Rip1K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH. Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

scholarly journals K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yong Tang ◽  
Hailin Tu ◽  
Jie Zhang ◽  
Xueqiang Zhao ◽  
Yini Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Control Cell ◽  
Embryonic Lethality ◽  
Interacting Protein ◽  
Early Embryonic Lethality ◽  
Massive Cell Death ◽  
Massive Cell ◽  
Dependent Signaling Pathway

Abstract Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. However, how its kinase activity is regulated remains poorly understood. Here, we generate Ripk1K376R/K376R knock-in mice in which the Lys(K)63-linked ubiquitination of RIPK1 is impaired. The knock-in mice display an early embryonic lethality due to massive cell death that is resulted from reduced TAK1-mediated suppression on RIPK1 kinase activity and forming more TNFR1 complex II in Ripk1K376R/K376R cells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality of Ripk1K376R/K376R mice. Notably, Ripk1K376R/- mice are viable but develop severe systemic inflammation that is mainly driven by RIPK3-dependent signaling pathway, indicating that K63-linked ubiquitination on Lys376 residue of RIPK1 also contributes to inflammation process. Together, our study reveals the mechanism by which K63-linked ubiquitination on K376 regulates RIPK1 kinase activity to control cell death programs.

scholarly journals The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Christa Park ◽  
Kazuha Koyama ◽  
Sakthi Balaji ◽  
Kohei Kita ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
Survival Function ◽  
Immune Homeostasis ◽  
Loss Of Function ◽  
Colonic Inflammation ◽  
Interacting Protein ◽  
Hematopoietic Stem ◽  
Bowel Diseases ◽  
Promote Cell Survival

AbstractReceptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C+ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.

scholarly journals TWEAK and RIPK1 mediate a second wave of cell death during AKI

2018 ◽  
Vol 115 (16) ◽  
pp. 4182-4187 ◽  
Author(s):  
Diego Martin-Sanchez ◽  
Miguel Fontecha-Barriuso ◽  
Susana Carrasco ◽  
Maria Dolores Sanchez-Niño ◽  
Anne von Mässenhausen ◽  
...  
Keyword(s):  
Cell Death ◽  
Kidney Injury ◽  
Early Time ◽  
Therapeutic Window ◽  
Kidney Dysfunction ◽  
Interacting Protein ◽  
Cell Death Pathways ◽  
Caspase Inhibition ◽  
Regulated Necrosis ◽  
Second Wave

Acute kidney injury (AKI) is characterized by necrotic tubular cell death and inflammation. The TWEAK/Fn14 axis is a mediator of renal injury. Diverse pathways of regulated necrosis have recently been reported to contribute to AKI, but there are ongoing discussions on the timing or molecular regulators involved. We have now explored the cell death pathways induced by TWEAK/Fn14 activation and their relevance during AKI. In cultured tubular cells, the inflammatory cytokine TWEAK induces apoptosis in a proinflammatory environment. The default inhibitor of necroptosis [necrostatin-1 (Nec-1)] was protective, while caspase inhibition switched cell death to necroptosis. Additionally, folic acid-induced AKI in mice resulted in increased expression of Fn14 and necroptosis mediators, such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage domain-like protein (MLKL). Targeting necroptosis with Nec-1 or by genetic RIPK3 deficiency and genetic Fn14 ablation failed to be protective at early time points (48 h). However, a persistently high cell death rate and kidney dysfunction (72–96 h) were dependent on an intact TWEAK/Fn14 axis driving necroptosis. This was prevented by Nec-1, or MLKL, or RIPK3 deficiency and by Nec-1 stable (Nec-1s) administered before or after induction of AKI. These data suggest that initial kidney damage and cell death are amplified through recruitment of inflammation-dependent necroptosis, opening a therapeutic window to treat AKI once it is established. This may be relevant for clinical AKI, since using current diagnostic criteria, severe injury had already led to loss of renal function at diagnosis.

Sign in / Sign up

Export Citation Format

Share Document