Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer

Annibaldi, Alessandro; Meier, Pascal

doi:10.1016/j.molmed.2017.11.002

Cited by 223 publications

(232 citation statements)

References 119 publications

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“…The participation of IKKβ in TNF‐mediated cell death could occur at a point of either NF‐κB‐dependent or ‐independent . In this study, we found that 3AR‐C sensitized RIPK1‐dependent apoptosis and necroptosis upon TNFR1 ligation by inhibiting IKKβ.…”

Section: Discussionmentioning

confidence: 54%

“…The participation of IKKβ in TNF-mediated cell death could occur at a point of either NF-κB-dependent or -independent. 16,17 In this study, we found that 3AR-C sensitized RIPK1-dependent apoptosis and necroptosis upon TNFR1 ligation by inhibiting IKKβ. Consistently, we also found that such dual modes of cell death by 3AR-C/TNF were completely abrogated in RIPK1-null MEFs (Figure 2).…”

Section: Discussionmentioning

confidence: 54%

“…At present, it is believed that there are additional transcription-independent early cell death checkpoints regulated by phosphorylation of RIPK1. 16,17 Consistent with this possibility, genetic deletion or pharmacological inhibition of TAK1 and IKKα/β resulted in further sensitization of cell death by activating RIPK1, independently of NF-κB activation. 18,19 Subsequent biochemical analyses revealed that RIPK1 phosphorylation on Ser 321 or Ser 25 by TAK1 or IKKα/β in complex-I prevented the RIPK1-mediated assembly of the complex-II/necrosome and then inhibited apoptosis/necroptosis in an NF-κBindependent manner.…”

Section: Introductionmentioning

confidence: 82%

“…NF‐κB‐mediated transcriptional induction of pro‐survival genes is a well‐known protective mechanism against cell death that occurs as a late checkpoint. At present, it is believed that there are additional transcription‐independent early cell death checkpoints regulated by phosphorylation of RIPK1 . Consistent with this possibility, genetic deletion or pharmacological inhibition of TAK1 and IKKα/β resulted in further sensitization of cell death by activating RIPK1, independently of NF‐κB activation .…”

Section: Introductionmentioning

confidence: 90%

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3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 90%

See 2 more Smart Citations

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

et al. 2020

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“…Other innate immune kinases, such as IRAK1 (Interleukin‐1 (IL‐1) receptor‐associated kinase 1) and IRAK4, are ubiquitination targets for other Ub ligases such as TRAF6 and Pellino1 in TLR/IL‐1R signaling (Cohen & Strickson, ). Remarkably, knowledge about the substrates of RIPK and IRAK kinases is limited and there is a continuing debate about the role of these proteins as true kinases versus their scaffolding function, including as scaffolds for ubiquitination (Kawagoe et al , ; Kim et al , ; Koziczak‐Holbro et al , ; Ordureau et al , ; Song et al , ; Vollmer et al , ; Wang et al , ; Annibaldi & Meier, ; Dziedzic et al , ). Our findings for RIPK2 exemplify the cross‐talk between the kinase domain serving as a binding interface for a Ub ligase (XIAP) and kinase inhibitors acting as blockers of this interaction.…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

et al. 2018

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RIPK2 mediates inflammatory signaling by the bacteria‐sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD‐mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP‐binding and XIAP‐mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N‐lobe of the kinase, which is in close proximity to the ATP‐binding pocket. Through characterization of a new series of ATP pocket‐binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2‐XIAP interaction, and of cellular and in vivo NOD2 signaling. Our study exemplifies how targeting of the ATP‐binding pocket in RIPK2 can be exploited to interfere with the RIPK2‐XIAP interaction for modulation of NOD signaling.

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Targeting immunogenic cell death in cancer

2020

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Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. Remarkably, subcutaneous injection of dying tumor cells undergoing ICD has been shown to provoke anticancer vaccine effects in vivo. DAMPs include the cell surface exposure of calreticulin (CRT) and heat-shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), type I IFNs and members of the IL-1 cytokine family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy.

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Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer

Cited by 223 publications

References 119 publications

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

Targeting immunogenic cell death in cancer

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