Killing AML: RIPK3 leads the way

Höckendorf, Ulrike; Yabal, Monica; Jost, Philipp J.

doi:10.1080/15384101.2016.1232069

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…Also in resected colon cancer, gastric cancer, cervical cancer and ovarian cancer similar correlations were observed [94][95][96][97][98]. Additionally, breast cancer and several subtypes of acute myeloid leukemia (AML) have reduced MLKL mRNA expression [18,[99][100][101]. The downregulation of RIPK3 and MLKL in AML suggests the existence of selective forces that propagate AML progression by inducing necroptosis-resistance [100,102].…”

Section: Mlkl As Anti-cancerous Factormentioning

confidence: 68%

MLKL in cancer: more than a necroptosis regulator

et al. 2021

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Mixed lineage kinase domain-like protein (MLKL) emerged as executioner of necroptosis, a RIPK3-dependent form of regulated necrosis. Cell death evasion is one of the hallmarks of cancer. Besides apoptosis, some cancers suppress necroptosis-associated mechanisms by for example epigenetic silencing of RIPK3 expression. Conversely, necroptosiselicited inflammation by cancer cells can fuel tumor growth. Recently, necroptosis-independent functions of MLKL were unraveled in receptor internalization, ligand-receptor degradation, endosomal trafficking, extracellular vesicle formation, autophagy, nuclear functions, axon repair, neutrophil extracellular trap (NET) formation, and inflammasome regulation. Little is known about the precise role of MLKL in cancer and whether some of these functions are involved in cancer development and metastasis. Here, we discuss current knowledge and controversies on MLKL, its structure, necroptosisindependent functions, expression, mutations, and its potential role as a pro-or anti-cancerous factor. Analysis of MLKL expression patterns reveals that MLKL is upregulated by type I/II interferon, conditions of inflammation, and tissue injury. Overall, MLKL may affect cancer development and metastasis through necroptosis-dependent and -independent functions.

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Section: Mlkl As Anti-cancerous Factormentioning

confidence: 68%

MLKL in cancer: more than a necroptosis regulator

et al. 2021

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“…showed that loss of the RIPK3 and MLKL signaling pathways has two effects. It promotes survival of transforming preleukemic hematopoietic stem and progenitor cells and also inhibits leukemia‐initiating cells differentiation along the myeloid lineage, leading to accumulation of leukemia‐initiating cells and thus leukemogenesis. Furthermore, it has been shown in a genetic mouse model of chronic hepatic inflammation induced by specific deletion of Tak1 in liver parenchymal cells that activation of RIPK3 inhibits tumor growth.…”

Section: The Necroptotic Pathway Is Affected In Many Cancersmentioning

confidence: 99%

Necroptotic cell death in anti‐cancer therapy

Krysko

Aaes

Kagan

et al. 2017

Immunological Reviews

141

103

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Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.

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“…Recently, multiple studies have suggested there are roles for necroptosis in development [2][3][4][5] and disease [reviewed in (6)(7)(8)], such as viral infection, 9 atherosclerosis, 10,11 renal ischemic reperfusion injury, 12 and cancer. [13][14][15] The extrinsic pathway of apoptosis is initiated by ligation of death receptors, a subset of the tumor necrosis factor superfamily (TNFRSF) that includes tumor necrosis factor (TNF) receptor-1 (TNFR1; It has become evident that there is a bridge between apoptosis and necroptosis in homeostasis and disease. [3][4][5] The extrinsic apoptotic and necroptotic pathways are tightly intertwined and depend on multiple proteins that regulate whether a cell (or animal) lives or dies.…”

Section: Introductionmentioning

confidence: 99%

Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

579

421

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Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

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Killing AML: RIPK3 leads the way

Cited by 3 publications

References 7 publications

MLKL in cancer: more than a necroptosis regulator

MLKL in cancer: more than a necroptosis regulator

Necroptotic cell death in anti‐cancer therapy

Caspase‐8: regulating life and death

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