Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment

Silvente-Poirot, Sandrine; Ségala, Grégory; Poirot, Mathias C.

doi:10.1080/15548627.2018.1425059

Cited by 25 publications

(26 citation statements)

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“…Interestingly, in tumor cells, the natural steroid Dendrogenin A has been shown to stimulate expression of Nur77 via binding to LXRβ and induce lethal autophagy ( 91 , 92 ), opening up new perspectives for cancer treatment ( 93 ). Moreover, it has been shown that Dendrogenin A, in addition to inducing growth control and improve overall survival in mice, also induces immune cell infiltration, including DCs, in the tumor ( 94 ).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

et al. 2018

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Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. Proper function of DCs is crucial to elicit an effective immune response against pathogens and to induce antitumor immunity. Different members of the nuclear receptor (NR) family of transcription factors have been reported to affect proper function of immune cells. Nur77 is a member of the NR4A subfamily of orphan NRs that is expressed and has a function within the immune system. We now show that Nur77 is expressed in different murine DCs subsets in vitro and ex vivo, in human monocyte-derived DCs (moDCs) and in freshly isolated human BDCA1+ DCs, but its expression is dispensable for DC development in the spleen and lymph nodes. We show, by siRNA-mediated knockdown of Nur77 in human moDCs and by using Nur77−/− murine DCs, that Nur77-deficient DCs have enhanced inflammatory responses leading to increased T cell proliferation. Treatment of human moDCs with 6-mercaptopurine, an activator of Nur77, leads to diminished DC activation resulting in an impaired capacity to induce IFNγ production by allogeneic T cells. Altogether, our data show a yet unexplored role for Nur77 in modifying the activation status of murine and human DCs. Ultimately, targeting Nur77 may prove to be efficacious in boosting or diminishing the activation status of DCs and may lead to the development of improved DC-based immunotherapies in, respectively, cancer treatment or treatment of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

et al. 2018

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“…In the case of melanoma cells treated with THPN, a chemical compound targeting NR4A1, cell death occurs after induction of excessive mitophagy, due to NR4A1 translocation to the inner membrane of the mitochondria, causing dissipation of mitochondrial membrane potential by the permeability pore complex ANT1/VDAC [14]. Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo [15,16], displaying anticancer and chemopreventive properties in mice [17]. Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death [18], which seems to be mediated by releasing BECN1 in a model of cigarette smokeinduced autophagic cell death [19].…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

et al. 2020

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NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and posttranslational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.

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“…In the case of melanoma cells treated with THPN, a chemical compound targeting NR4A1, cell death occurs after induction of excessive mitophagy, due to NR4A1 translocation to the inner membrane of the mitochondria, causing dissipation of mitochondrial membrane potential by the permeability pore complex ANT1/VDAC (14). Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo (15, 16), displaying anticancer and chemopreventive properties in mice(17). Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death (18), which seems to be mediated by releasing BECN1 in a model of cigarette smoke-induced autophagic cell death(19).…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

Castro-Obregón

Zárraga

Muciño-Hernández

et al. 2019

Preprint

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242 25 Abstract 26 NR4A is a nuclear receptor protein family whose members act as sensors of cellular 27 environment and regulate multiple processes such as metabolism, proliferation, migration, 28 apoptosis, and autophagy. Since the ligand binding domains of these receptors have no 29 cavity for ligand interaction, their function is most likely regulated by protein abundance 30 and post-translational modifications. In particular, NR4A1 is regulated by protein 31 abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic 32 translocation), and acts both as a transcription factor and as a regulator of other 33 interacting proteins. SUMOylation is a post-translational modification that can affect protein 34 stability, transcriptional activity, alter protein-protein interactions and modify intracellular 35 localization of target proteins. In the present study we evaluated the role of SUMOylation 36 as a posttranslational modification that can regulate the activity of NR4A1 to induce 37 autophagy-dependent cell death. We focused on a model potentially relevant for neuronal 38 cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic 39 cell death. We observed that a triple mutant in SUMOylation sites has reduced 40 SUMOylation, increased transcriptional activity, altered intracellular distribution, and more 41 importantly, its ability to induce autophagic cell death is impaired. 42 43 Summary Statement 44 The modification of the nuclear receptor NR4A1 by SUMO regulates its transcriptional 45 activity, intracellular localization and is required to induce autophagic cell death.46 47 Short title: SUMOylated NR4A1 induces autosis 48 49 Keywords: 50 NR4A1, SUMO, autophagy, cell death, Substance P, NK 1 R3 51 52 Abbreviations list 53 NR4A Nuclear receptor group family A 54 NR4A1 Nuclear receptor group 4 family A member 1 (Nur77, NGF1B, TR3, etc.) 55 NR4A2 Nuclear receptor group 4 family A member 2 (Nurr1, NOT1, etc) 56 NR4A3 Nuclear receptor group 4 family A member 3 (Nor1, MINOR) 57 SUMO small ubiquitin-like modifier 58 SP Substance P 59 NK 1 R Neurokinin 1 Receptor 60 TAD Trans-Activation Domain 61 DBD DNA Binding Domain 62 LBD Ligand Binding Domain 63 PTM Post Translational Modifications 4 64 Introduction 65 Nuclear receptors are a superfamily of transcription factors involved in a vast number of 66 biological processes. They share three common structural domains: a N-terminal 67 transactivation domain (TAD), a central double zinc finger DNA binding domain (DBD) and 68 a C-terminal ligand binding domain (LBD). Among the known human nuclear receptors, 69 the ones belonging to the NR4A family act as sensors of the cellular environment and 70 contribute to cell fate decisions, such as cell proliferation, differentiation, migration, cell 71 death, etc. Physiologically, NR4A members influence the adaptive and innate immune 72 system, angiogenesis, metabolism and brain function. The NR4A family is comprised of 73 three members that bind the same DNA elements (1): NR4A1 (Nur77, TR3, ...

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Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment

Cited by 25 publications

References 0 publications

Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

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