zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

Yt, Wu; Hl, Tan; Huang, Qing; Sun, Xueying; Zhu, Xiaoyan; Shen, Han‐Ming

doi:10.1038/cdd.2010.72

Cited by 165 publications

(168 citation statements)

References 41 publications

(66 reference statements)

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD, [22][23][24] caspase-8, RIP1, and RIP3, and the cells undergo necroptosis. 25,26 Caspase-8 and FADD negatively regulates necroptosis, [27][28][29][30] because RIP1, RIP3, and CYLD are potential substrates of caspase-8. [31][32][33][34] Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet.…”

mentioning

confidence: 99%

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

258

230

View full text Add to dashboard Cite

Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis. Cell Death and Differentiation (2014) 21, 1709-1720; doi:10.1038/cdd.2014.77; published online 6 June 2014Necroptosis is a type of programmed necrosis characterized by necrotic morphological changes, including cellular organelle swelling, cell membrane rupture, 1-3 and dependence of receptor-interacting protein (RIP)1 4 and RIP3. [5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, 12-16 tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis. If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD, [22][23][24] caspase-8, RIP1, and RIP3, and the cells undergo necroptosis. 25,26 Caspase-8 and FADD negatively regulates necroptosis, 27-30 because RIP1, RIP3, and CYLD are potential substrates of caspase-8. [31][32][33][34] Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (ML...

show abstract

mentioning

confidence: 99%

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

258

230

View full text Add to dashboard Cite

show abstract

“…Similar to L929 cells, CT26 cells can be sensitized by polyI:C to induce necroptosis in the presence of zVAD (24). However, this result cannot always be generalized for the other tumor cell lines (Supplementary Table S2 and Fig.…”

Section: Discussionmentioning

confidence: 93%

“…The expression levels of RIP3 is lower in B16D8 cells (resistant to the polyI:C-induced cell death) than in wild-type CT26 and L929 cells (Fig. 5F), in which necroptosis can be induced (24). The RIP3 protein expression levels are clearly different between necroptosis-resistant CT26 cells and the parent CT26 cells (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…To determine whether polyI:C or combination of polyI:C/zVAD could induce cell death in tumor cell lines, we added these reagents to the culture of mouse tumor cell lines, including YAC-1, EL-4, B16F1, B16F10, B16D8, Renca, G1, G5, 3LL, MC38, and CT26. The L929 fibroblast cell line was used as a positive control for cell death (24). Cell viability was measured by the WST-1 assay (Supplementary Table S2).…”

Section: Necroptosis Induced By Polyi:c and Zvadmentioning

confidence: 99%

See 1 more Smart Citation

PolyI:C–Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector–Mediated Tumor Elimination In Vivo

Takemura

Takaki

Okada

et al. 2015

Cancer Immunology Research

View full text Add to dashboard Cite

Double-stranded RNA directly acts on fibroblast and myeloid lineages to induce necroptosis as in TNFa. Here, we investigated whether this type of cell death occurred in cancer cells in response to polyinosinic-polycytidylic acid (polyI:C) and the pan-caspase inhibitor z-Val-Ala-Asp fluromethyl ketone (zVAD). We found that the colon cancer cell line CT26 is highly susceptible to necroptosis, as revealed by staining with annexin V/propidium iodide. CT26 cells possess RNA sensors, TLR3 and MDA5, which are upregulated by interferon (IFN)-inducing pathways and linked to receptor-interacting protein kinase (RIP) 1/3 activation via TICAM-1 or MAVS adaptor, respectively. Although exogenously added polyI:C alone marginally induced necroptosis in CT26 cells, a combined regimen of polyI:C and zVAD induced approximately 50% CT26 necroptosis in vitro without secondary effects of TNFa or type I IFNs. CT26 necroptosis depended on the TLR3-TICAM-1-RIP3 axis in the tumor cells to produce reactive oxygen species, but not on MDA5, MAVS, or the caspases/inflammasome activation. However, the RNA-derived necroptosis was barely reproduced in vivo in a CT26 tumor-implanted Balb/c mouse model with administration of polyI:C þ zVAD. Significant shrinkage of CT26 tumors was revealed only when polyI:C (100 mg) was injected intraperitoneally and zVAD (1 mg) subcutaneously into tumor-bearing mice that were depleted of cytotoxic T lymphocytes and natural killer cells. The results were confirmed with immune-compromised mice with no lymphocytes. Although necroptosis-induced tumor growth retardation appears mechanistically complicated and dependent on the injection routes of polyI:C and zVAD, anti-caspase reagent directed to tumor cells will make RNA adjuvant immunotherapy more effective by modulating the formation of the tumoricidal microenvironment and dendritic cell-inducing antitumor immune system.

show abstract

“…The physiological relevance of necroptosis has been a common debate since its discovery because the phenomenon is usually observed only upon pharmacologic (zVAD-fmk) or genetic (Apaf-1 or FADD knockout) inhibition of the apoptotic pathway (Shiraishi et al, 2010;Wu et al, 2011;Zhang et al, 2011). This apparent overshadowing of necroptosis by apoptosis implies that apoptotic death is the first choice in most settings and that necroptosis acts only as a safeguard alternative to ensure cell demise is inevitable should the apoptotic machinery fail.…”

Section: Is Necroptosis Just a Backup Suicide Route When Apoptosis Famentioning

confidence: 99%

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

2012

View full text Add to dashboard Cite

zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

Cited by 165 publications

References 41 publications

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

PolyI:C–Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector–Mediated Tumor Elimination In Vivo

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

Contact Info

Product

Resources

About