ReferenceID 4422
8-Geranylumbelliferone isolated from Paramignya trimera triggers RIPK1/RIPK3-dependent programmed cell death upon TNFR1 ligation
Biochem Pharmacol
In tumor necrosis factor (TNF) signaling, IkappaB kinase (IKK) complex-mediated activation of NF-kappaB is a well-known protective mechanism against cell death via transcriptional induction of pro-survival genes occurrin
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Record Fields
Scalar fields from the final reference record.
- Reference Id
- 4422
- Evidence Id
- 21012
- Core Evidence Id
- 21012
- Source Reference Id
- 2125
- Herb2 Reference Id
- HBREF002922
- Subject Paper Key
- HBIN013734_34411570
- Pubmed Id
- 34411570
- Doi
- 10.1016/j.bcp.2021.114733
- Paper Title
- 8-Geranylumbelliferone isolated from Paramignya trimera triggers RIPK1/RIPK3-dependent programmed cell death upon TNFR1 ligation
- Paper Abstract
- In tumor necrosis factor (TNF) signaling, IkappaB kinase (IKK) complex-mediated activation of NF-kappaB is a well-known protective mechanism against cell death via transcriptional induction of pro-survival genes occurring as a late checkpoint. However, recent belief holds that IKK functions as an early cell death checkpoint to suppress the death-inducing signaling complex by regulating receptor interacting protein kinase1 (RIPK1) phosphorylation. In this study, we propose that two major gernaylated 7-hydroxy coumarins, 6-geranyl-7-hydroxycoumarin (ostruthin) and 8-geranyl-7-hydroxycoumarin (8-geranylumbelliferone, 8-GU) isolated from Paramignya timera, facilitate RIPK1-dependent dual modes of apoptosis and necroptosis by targeting IKKbeta upon TNF receptor1 (TNFR1) ligation. Analysis of events upstream of NF-kappaB revealed that 8-GU and ostruthin drastically inhibited TNF-induced IKK phosphorylation, while having no effect on TAK1 phosphorylation and TNFR1 complex-I formation. Interestingly, 8-GU did not affect the cell death induced by Fas ligand or TNF-related apoptosis-inducing ligand or that induced by DNA-damaging agents, indicating that 8-GU sensitizes TNF-induced cell death exclusively. Moreover, 8-GU accelerated TNF-driven necroptosis by up-regulating necrosome formation in FADD deficient cancer cells harboring RIPK3. Thus, the present study provides new insights into the molecular mechanism underlying geranylated 7-hydroxy coumarin-mediated control of the RIPK1-dependent early cell death checkpoint and suggests that 8-GU is a potential anti-cancer therapeutic via an alternative apoptosis-independent strategy to overcome TNF resistance.
- Journal
- Biochem Pharmacol
- Publish Year
- 2021
- Experiment Subject
- Experiment Type
- Cell Experiment
- Phenotype Related
- Tumor; Fadd Deficient Cancer
- Paper Title Cn
- Paper Title En
- 8-Geranylumbelliferone isolated from Paramignya trimera triggers RIPK1/RIPK3-dependent programmed cell death upon TNFR1 ligation
- Bilingual Status
- semi_complete