RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

Patel, Snahel; Webster, Joshua D.; Varfolomeev, Eugene; Kwon, Youngsu; Cheng, Jill; Zhang, J.; Dugger, Debra L.; Wickliffe, Katherine E.; Maltzman, Allie; Sujatha-Bhaskar, Swathi; Kohli, Pawan Bir; Ramaswamy, Sreemathy; Deshmukh, Gauri; Liederer, Bianca M.; Fong, R.; Hamilton, Gregory L.; Lupardus, P.J.; Caplazi, Patrick; Lee, W.P.; Campagne, Menno van Lookeren; Johnson, A. Peter; McKenzie, Brent; Junttila, Melissa R.; Newton, Kim; Vucic, Domagoj

doi:10.1038/s41418-019-0347-0

Cited by 110 publications

(146 citation statements)

References 53 publications

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“…Although necroptosis has been proposed as an alternative means of controlling viral infections when caspase activity is inhibited, it has also been suggested to promote chronic inflammatory diseases by sustaining the proinflammatory environment. As such, RIP1's kinase function has been proposed as a potential therapeutic target for acute and chronic inflammatory diseases …”

Section: Introductionmentioning

confidence: 99%

RIP1 kinase activity is critical for skin inflammation but not for viral propagation

Webster¹,

Kwon²,

Park³

et al. 2020

Journal of Leukocyte Biology

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Receptor interacting protein kinase 1 (RIP1) is a critical effector of inflammatory responses and cell death activation. Cell death pathways regulated by RIP1 include caspase‐dependent apoptosis and caspase‐independent necroptosis. The kinase activity of RIP1 has been associated with a number of inflammatory, neurodegenerative, and oncogenic diseases. In this study, we use the RIP1 kinase inhibitor GNE684 to demonstrate that RIP1 inhibition can effectively block skin inflammation and immune cell infiltrates in livers of Sharpin mutant (Cpdm; chronic proliferative dermatitis) mice in an interventional setting, after disease onset. On the other hand, genetic inactivation of RIP1 (RIP1 KD) or ablation of RIP3 (RIP3 KO) or MLKL (MLKL KO) did not affect testicular pathology of aging male mice. Likewise, infection with vaccinia virus or with mouse gammaherpesvirus MHV68 resulted in similar viral clearance in wild‐type, RIP1 KD, and RIP3 KO mice. In summary, this study highlights the benefits of inhibiting RIP1 in skin inflammation, as opposed to its lack of relevance for testicular longevity and the response to certain viral infections.

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Section: Introductionmentioning

confidence: 99%

RIP1 kinase activity is critical for skin inflammation but not for viral propagation

Webster¹,

Kwon²,

Park³

et al. 2020

Journal of Leukocyte Biology

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“…Apart from S161, none of the other residues seemed to have a major effect on cell death induction 40 . While RIPK1 autophosphorylation at S166 is commonly employed as a biomarker of RIPK1 kinase activity 10,21,35,41 , the functional role and mechanism of action of this autophosphorylation site remains elusive.…”

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confidence: 99%

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

et al. 2020

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Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

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“…TAK1 inhibition sensitized melanoma cells to apoptosis induced by a combination of TNF-α and TRAIL [144], indicating that TAK1 regulated apoptosis-related role of RIPK1 in melanoma. In addition, inhibition of RIPK1 and loss of RIPK3 did not reduce lung metastasis in a mouse model of melanoma [145]. In another study, however, pre-treatment of mice with necrostatin-1 or a novel RIPK1 inhibitor, PK68, significantly suppressed lung metastasis by melanoma cells [146], suggesting that further research is needed to clarify the role of RIPK1 in melanoma progression.…”

Section: Necroptosis In Melanomamentioning

confidence: 93%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

Cited by 110 publications

References 53 publications

RIP1 kinase activity is critical for skin inflammation but not for viral propagation

RIP1 kinase activity is critical for skin inflammation but not for viral propagation

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

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