期刊
FASEB JOURNAL
卷 34, 期 3, 页码 4369-4383出版社
WILEY
DOI: 10.1096/fj.201902547R
关键词
apoptosis; IKK beta; necroptosis; phosphorylation; RIPK1; TNF; 3AR-C
资金
- National Research Foundation of Korea (NRF) [2017R1A2A1A05001225, 2017R1A5A2015385, 2017R1A2A2A05001340]
- National Research Foundation of Korea [2017R1A2A2A05001340, 2017R1A2A1A05001225] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 IKK beta. Notably, 3AR-C did not interfere with IKK alpha 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 IKK beta phosphorylation and promotion of the cytotoxic potential of RIPK1, thus providing a rationale for further development of 3AR-C as a selective IKK beta inhibitor to overcome TNF resistance in cancer therpay.
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