TRAIL-receptor 2—a novel negative regulator of p53

Willms, Anna; Schupp, Hella; Poelker, Michelle; Adawy, Alshaimaa; Debus, Jan Frederik; Hartwig, Torsten; Krichel, Tim; Fritsch, Jürgen; Singh, Steven; Walczak, Henning; Karstedt, Silvia von; Schäfer, Heiner; Trauzold, Anna

doi:10.1038/s41419-021-04048-1

Cited by 15 publications

(11 citation statements)

References 46 publications

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“…It is noteworthy that both TRAIL-R2 and DcR1 receptors are p53 target genes [29] and, while is clear that TRAIL-R2 upregulation is depending upon p53 activation [49], the requirement of TRAIL-R2 during p53mediated apoptosis remains still unclear. However, more recently nuclear TRAIL-R2 has been shown to act as a negative regulator of p53, suggesting that it may heavily impact, for example, on tumor growth [50]. Despite these ndings, we found that the p53 expression was blunted in TRAIL-R -/mice treated with Aβ1-42, suggesting that TRAIL-R2 contributes, in turn, to p53 mediation of Aβ-induced neurotoxicity.…”

Section: Discussioncontrasting

confidence: 75%

TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

Benedetto

Burgaletto

Serapide

et al. 2021

Preprint

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TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells undergone treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β protein. Likewise, TRAIL-R2 appears essential to both TRAIL-Aβ mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice, challenged with Aβ1-42, showed a scanty expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-a, iNOS and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

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Section: Discussioncontrasting

confidence: 75%

TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

Benedetto

Burgaletto

Serapide

et al. 2021

Preprint

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“…This is partially due to the fact that after its identification, it was found that several cancer cell lines and primary cancer cells gained TRAIL resistance [ 7 ]. Moreover, it has been reported that TRAIL-R2 can also have pro-oncogenic properties, such as in cancer cells with oncogenic mutations in the Kirsten rat sarcoma virus (KRAS) [ 8 ] or wild-type p53 gene [ 9 ]. Therefore, a better understanding of the cancer cell TRAIL/TRAIL-R apoptosis mechanism and gained resistance will be crucial for the development of TRAIL-related anti-cancer drugs [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Astaxanthin Sensitizes Low SOD2-Expressing GBM Cell Lines to TRAIL Treatment via Pathway Involving Mitochondrial Membrane Depolarization

et al. 2022

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Carotenoids have been suggested to have either anti- or pro-oxidative effects in several cancer cells, and those effects can trigger an unbalanced reactive oxygen species (ROS) production resulting in an apoptotic response. Our study aimed to evaluate the effect of the well-known carotenoid 3, 3′-dihydroxy-β, β’-carotene-4, 4-dione (astaxanthin, AXT) on glioblastoma multiforme (GBM) cells, especially as a pretreatment of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), that was previously shown to increase ROS and to induce apoptosis in cancer cells. We found that AXT by itself did not trigger apoptosis in four investigated GBM cell lines upon a 24 h treatment at various concentrations from 2.5 to 50 µM. However, in U251-MG and T98-MG GBM cells, pretreatment of 2.5 to 10 µM AXT sensitized cells to TRAIL treatment in a statistically significant manner (p < 0.05) while it did not affect CRT-MG and U87-MG GBM cells. We further compared AXT-sensitive U251-MG and -insensitive CRT-MG response to AXT and showed that 5 µM AXT treatment had a beneficial effect on both cell lines, as it enhanced mitochondrial potential and TRAIL treatment had the opposite effect, as it decreased mitochondrial potential. Interestingly, in U251-MG, 5 µM AXT pretreatment to TRAIL-treated cells mitochondrial potential further decreased compared to TRAIL alone cells. In addition, while 25 and 50 ng/mL TRAIL treatment increased ROS for both cell lines, pretreatment of 5 µM AXT induced a significant ROS decrease in CRT-MG (p < 0.05) while less effective in U251-MG. We found that in U251-MG, superoxide dismutase (SOD) 2 expression and enzymatic activity were lower compared to CRT-MG and that overexpression of SOD2 in U251-MG abolished AXT sensitization to TRAIL treatment. Taken together, these results suggest that while AXT acts as an ROS scavenger in GBM cell lines, it also has some role in decreasing mitochondrial potential together with TRAIL in a pathway that can be inhibited by SOD2.

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“…It is noteworthy that both TRAIL-R2 and DcR1 receptors are p53 target genes [ 29 ] and, while is clear that TRAIL-R2 upregulation depend upon p53 activation [ 46 ], the requirement of TRAIL-R2 during p53-mediated apoptosis remains still unclear. However, more recently, nuclear TRAIL-R2 has been shown to act as a negative regulator of p53, suggesting that it may heavily impact, for example, tumour growth [ 47 ]. Despite these findings, we found that the p53 expression was blunted in TRAIL-R −/− mice treated with oligomeric Aβ1-42, suggesting that TRAIL-R2 contributes, in turn, to p53 mediation of Aβ-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-β

Benedetto

Burgaletto

Serapide

et al. 2022

IJMS

View full text Add to dashboard Cite

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R−/−). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R−/− mouse embryonic hippocampal cells after treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R−/− mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aβ-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R−/− mice challenged with Aβ1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

show abstract

TRAIL-receptor 2—a novel negative regulator of p53

Cited by 15 publications

References 46 publications

TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

Astaxanthin Sensitizes Low SOD2-Expressing GBM Cell Lines to TRAIL Treatment via Pathway Involving Mitochondrial Membrane Depolarization

TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-β

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