The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

Ortiz-Ferrón, Gustavo; Tait, Stephen W.G.; Robledo, Gema; Vries, Evert de; Borst, Jannie; López‐Rivas, Abelardo

doi:10.1038/sj.cdd.4401875

Cited by 17 publications

(13 citation statements)

References 44 publications

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“…It is important to point out that, in addition to the overexpression of XIAP and a lack of p53 signaling, a dysfunction of DR4 and DR5, a defect in any components of the extrinsic apoptotic cascade, 54-57 the overexpression of antiapoptotic Bcl-2 and loss of function of proapoptotic Bcl-2 proteins, [58][59][60] and the activation of mitogen-activated protein kinase (MAPK) 61 or NF-B signaling 62,63 can all contribute to TRAIL resistance. Therefore, it is difficult to single out which particular protein or set of proteins results in diminished or absent sensitization to the combination.…”

Section: Discussionmentioning

confidence: 99%

Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Carter

Mak

Schober

et al. 2008

Blood

122

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Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor ␣-related apoptosis-inducing ligand (TRAIL). We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells, and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAILinduced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance.

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Section: Discussionmentioning

confidence: 99%

Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Carter

Mak

Schober

et al. 2008

Blood

122

View full text Add to dashboard Cite

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“…Rab5a (DKFZ clone repository, NM_004162) was amplified and inserted into pmCherry-C1 to generate mCherry-Rab5. To generate Bid sensor, mCherry was fused to full-length Bid (obtained from Ortiz-Ferrón et al (26)) at the N terminus, and GFP was fused in-frame to the C terminus of Bid. The caspase 8-insensitive Bid⌬60 sensor was obtained using site-directed mutagenesis to generate the D60A mutation (27).…”

Section: Methodsmentioning

confidence: 99%

Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production

Hamacher-Brady

Stein

Turschner

et al. 2011

Journal of Biological Chemistry

204

170

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The antimalarial agent artesunate (ART) activates programmed cell death (PCD) in cancer cells in a manner dependent on the presence of iron and the generation of reactive oxygen species. In malaria parasites, ART cytotoxicity originates from interactions with heme-derived iron within the food vacuole. The analogous digestive compartment of mammalian cells, the lysosome, similarly contains high levels of redox-active iron and in response to specific stimuli can initiate mitochondrial apoptosis. We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization. Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. ART killing did not involve activation of the BH3-only protein, Bid, yet ART enhanced TNF-mediated Bid cleavage. We additionally demonstrated the lysosomal PCD pathway in T47D and MDA-MB-231 breast cancer cells. Importantly, non-tumorigenic MCF-10A cells resisted ARTinduced PCD. Together, our data suggest that ART triggers PCD via engagement of distinct, interconnected PCD pathways, with hierarchical signaling from lysosomes to mitochondria, suggesting a potential clinical use of ART for targeting lysosomes in cancer treatment.Artemisinin, the active principle of the Chinese medicinal herb Artemisia annua L., and its water-soluble derivative, artesunate (ART), 3 are potent antimalarial treatments (1). Additionally, these compounds selectively activate programmed cell death (PCD) in cancer cells (2-4) and inhibit angiogenesis in both in vitro and in vivo models (7). Importantly, preliminary in vivo investigations indicate a therapeutic potential for cancer treatment (5-7), and clinical studies have already shown an excellent safety record in malaria treatment (8). Successful compassionate use of ART in uveal melanoma patients indicates its potential for cancer therapy (9). Components of canonical PCD pathways have been implicated in ART-activated cell death, including p53 (10), Bcl2 family-mediated mitochondrial dysfunction (10, 11), and enhanced reactive oxygen species (ROS) production (12-14). However, detailed understanding of the molecular mechanisms and the sequence of events during ART-induced cell death in cancer cells is limited.The malaria parasite digests iron-rich hemoglobin in its acidic food vacuole, and the interaction of ART with hemederived iron results in lethal ROS generation (15). The parasite food vacuole is analogous...

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“…A plasmid expressing the fusion protein full-length Bid (corresponding to 1-195 amino acid)/enhanced green fluorescent protein (EGFP) was kindly provided by A Lopez-Rivas (Ortiz-Ferron et al, 2006). The plasmid expressing the fusion protein-truncated Bid (corresponding to 61-195 amino acid)/ EGFP was obtained by modifying the above construct.…”

Section: Tbid-gfp Plasmid Constructmentioning

confidence: 99%

A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma

et al. 2008

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A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAILinduced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the deathinducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAILinduced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.

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The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

Cited by 17 publications

References 44 publications

Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production

A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma

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