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3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ
- Source :
- The FASEB Journal. 34:4369-4383
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- In tumor necrosis factor (TNF) signaling, phosphorylation and activation of receptor interacting protein kinase 1 (RIPK1) by upstream kinases is an essential checkpoint in the suppression of TNF-induced cell death. Thus, discovery of pharmacological agents targeting RIPK1 may provide new strategies for improving the therapeutic efficacy of TNF. In this study, we found that 3-O-acetylrubianol C (3AR-C), an arborinane triterpenoid isolated from Rubia philippinesis, promoted TNF-induced apoptotic and necroptotic cell death. To identify the molecular mechanism, we found that in mouse embryonic fibroblasts, 3AR-C drastically upregulated RIPK1 kinase activity by selectively inhibiting IKKβ. Notably, 3AR-C did not interfere with IKKα or affect the formation of the TNF receptor1 (TNFR1) complex-I. Moreover, in human cancer cells, 3AR-C was only sufficient to sensitize TNF-induced cell death when c-FLIPL expression was downregulated to facilitate the formation of TNFR1 complex-II and necrosome. Taken together, our study identified a novel arborinane triterpenoid 3AR-C as a potent activator of TNF-induced cell death via inhibition of IKKβ phosphorylation and promotion of the cytotoxic potential of RIPK1, thus providing a rationale for further development of 3AR-C as a selective IKKβ inhibitor to overcome TNF resistance in cancer therpay.
- Subjects :
- 0301 basic medicine
Programmed cell death
Magnetic Resonance Spectroscopy
Cell Survival
Necroptosis
Programmed Cell Death 1 Receptor
Apoptosis
Biochemistry
Mice
03 medical and health sciences
RIPK1
0302 clinical medicine
Cell Line, Tumor
Genetics
Animals
Humans
Kinase activity
Molecular Biology
Tumor Necrosis Factor-alpha
Kinase
Chemistry
I-kappa B Kinase
030104 developmental biology
Receptors, Tumor Necrosis Factor, Type I
Cancer research
Phosphorylation
Tumor necrosis factor alpha
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....da73a6110e1fbeaa8c7747536ba90af0