Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer

Feng, Xiaodong; Song, Qiancheng; Yu.Yu., Andreyeva; Tang, Heng Yuan; Peng, Zhuohui; Wang, X

doi:10.4149/neo_2015_071

Cited by 142 publications

(123 citation statements)

References 28 publications

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“…These findings correlate with observations that most cancer cell lines commonly used in the laboratory do not express RIPK3, which in response to chemotherapeutics represses programmed necrosis [27]. Moreover, overexpression of RIPK3 has been reported to suppress proliferation, migration and invasion of CRC cell lines [26]. These results support the idea that RIPK3 is critical in CRC as its expression might improve response to chemotherapy, and limit colorectal tumor initiation and progression.…”

Section: Introductionsupporting

confidence: 86%

“…Lack of RIPK3 in these cells was found to impair nuclear translocation of NF-κB subunit RelB-p50 and caspase-1-mediated pro-IL-1β processing [25]. More recently, RIPK3 expression has been shown to be downregulated in human CRC tissues when compared to adjacent normal tissues [26]. These findings correlate with observations that most cancer cell lines commonly used in the laboratory do not express RIPK3, which in response to chemotherapeutics represses programmed necrosis [27].…”

Section: Introductionmentioning

confidence: 99%

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Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis

et al. 2016

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Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.

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Section: Introductionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis

et al. 2016

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“…Nonetheless, since proteasome inhibition has the capacity to activate RIPK3 and MLKL in leukemia cell lines, it will be interesting to determine whether bortezomib can induce necroptosis in primary leukemia cells. RIPK3 expression was found to be decreased in various human cancer cell lines (23,43) as well as in primary colon cancer (23,44), breast cancer (45), and acute myeloid leukemia (46). Development of drugs to re-activate expression of RIPK3 in cancer cells may therefore synergize with proteasome inhibitors to enhance cancer cell death and treatment efficacy.…”

Section: Discussionmentioning

confidence: 99%

Regulation of RIPK3- and RHIM-dependent Necroptosis by the Proteasome

Moriwaki

Chan

2016

Journal of Biological Chemistry

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Receptor-interacting protein kinase 3 (RIPK3) is a serine/ threonine kinase with essential function in necroptosis. The activity of RIPK3 is controlled by phosphorylation. Once activated, RIPK3 phosphorylates and activates the downstream effector mixed lineage kinase domain-like (MLKL) to induce necroptosis. In certain situations, RIPK3 has also been shown to promote apoptosis or cytokine expression in a necroptosis and kinase-independent manner. The ubiquitin-proteasome system is the major pathway for selective degradation of cellular proteins and thus has a critical role in many cellular processes such as cell survival and cell death. Clinically, proteasome inhibition has shown promise as an anti-cancer agent. Here we show that the proteasome inhibitors MG132 and bortezomib activate the RIPK3-MLKL necroptotic pathway in mouse fibroblasts as well as human leukemia cells. Unlike necroptosis induced by classical TNF-like cytokines, necroptosis induced by proteasome inhibitors does not require caspase inhibition. However, an intact RIP homotypic interaction motif (RHIM) is essential. Surprisingly, when recruitment of MLKL to RIPK3 is restricted, proteasome inhibitors induced RIPK3-dependent apoptosis. Proteasome inhibition led to accumulation of K48-linked ubiquitinated RIPK3, which was partially reduced when Lys-264 was mutated. Taken together, these results reveal the ubiquitin-proteasome system as a novel regulatory mechanism for RIPK3-dependent necroptosis.Tissue homeostasis is maintained through dynamic balance between cell survival and cell death. A number of diseases such as cancer can be attributed to perturbation of this balance. Caspase-dependent apoptosis is a key cell death module with important functions in development and certain disease pathologies. In addition to apoptosis, recent evidence shows that a form of regulated necrosis, termed necroptosis, is significantly associated with a number of common clinical diseases such as viral infection, ischemia-reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases (1, 2). Necroptosis is driven by the cytosolic serine/threonine kinase receptor-interacting protein kinase 3 (RIPK3) 2 (3). A wide variety of stimuli including tumor necrosis factor (TNF) superfamily death ligands have been reported to induce necroptosis (1). Ligation of TNF to TNF receptor (TNFR) 1 causes formation of receptor-associated complex I, which comprises of TNFR1-associated via death domain (TRADD), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis 1 (cIAP1), cIAP2, linear ubiquitin chain assembly complex (LUBAC), and RIPK1. cIAPs and LUBAC promotes RIPK1 ubiquitination through Lys-11, Lys-63, and linear ubiquitin linkages, which promotes activation of NF-B and cell survival in part by limiting the formation of the cytosolic death-inducing signaling complex (DISC, aka complex IIa). Removal of the ubiquitin chains on RIPK1 by the de-ubiquitinase cylindromatosis (CYLD) promotes Complex IIa formation and apoptosis (4). When caspase 8 act...

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“…In a cohort of 112 patients with colorectal carcinoma, malignant cells exhibited reduced RIPK3 levels as compared with normal adjacent cells, and low RIPK3 expression constituted an independent prognostic factor for overall survival and disease-free survival (193, 194). Along similar lines, CD34 + blasts from 31 acute myeloid leukemia patients exhibited reduced levels of the RIPK3-coding mRNA as compared with CD34 + cells from healthy volunteers (195).…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

532

398

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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.

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Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer

Cited by 142 publications

References 28 publications

Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis

Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis

Regulation of RIPK3- and RHIM-dependent Necroptosis by the Proteasome

Necroptosis: Mechanisms and Relevance to Disease

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