The marine lipopeptide somocystinamide A triggers apoptosis via caspase 8

Wrasidlo, Wolf; Mielgo, Ainhoa; Torres, Vicente A.; Barbero, Simone; Stoletov, Konstantin; Suyama, Takashi; Klemke, Richard L.; Gerwick, William H.; Carson, Dennis A.; Stupack, Dwayne G.

doi:10.1073/pnas.0712198105

Cited by 108 publications

(66 citation statements)

References 35 publications

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“…In the absence of a mitochondrial pathway of apoptosis, a likely candidate for initiating the caspase cascade is caspase-8, required for death receptor-induced 23 and other forms of apoptosis. 11,24,25 We therefore asked whether caspase-8 was the apical caspase in glucose starvation-induced apoptosis in these cells. We generated a stable cell line expressing short hairpin RNA (shRNA) targeting caspase-8, and selected individual clones expressing low levels of caspase-8 ( Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…Caspase-8 is usually activated in a DISC complex formed upon ligation of death receptors. It is worth noting that caspase-8-dependent death has been described in response to stimuli other than death receptors, 11,24,25 which suggests that caspase-8 can be activated in 'alternative' platforms. It is unlikely that the classical death ligand-induced DISC is formed upon glucose deprivation, as blocking interactions between death receptors and their ligands did not block death.…”

Section: Discussionmentioning

confidence: 99%

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Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells

et al. 2010

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Apoptosis induced by most stimuli proceeds through the mitochondrial pathway. One such stimulus is nutrient deprivation. In this study we studied death induced by glucose deprivation in cells deficient in Bax and Bak. These cells cannot undergo mitochondrial outer membrane permeabilization (MOMP) during apoptosis, but they undergo necrosis when treated with MOMPdependent apoptotic stimuli. We find in these cells that glucose deprivation, rather than inducing necrosis, triggered apoptosis. Cell death required caspase activation as inhibition of caspases with peptidic inhibitors prevented death. Glucose deprivationinduced death displayed many hallmarks of apoptosis, such as caspase cleavage and activity, phosphatidyl-serine exposure and cleavage of caspase substrates. Neither overexpression of Bcl-xL nor knockdown of caspase-9 prevented death. However, transient or stable knockdown of caspase-8 or overexpression of CrmA inhibited apoptosis. Cell death was not inhibited by preventing death receptor-ligand interactions, by overexpression of c-FLIP or by knockdown of RIPK1. Glucose deprivation induced apoptosis in the human tumor cell line HeLa, which was prevented by knockdown of caspase-8. Thus, we have found that glucose deprivation can induce a death receptor-independent, caspase-8-driven apoptosis, which is engaged to kill cells that cannot undergo MOMP. Apoptosis is a form of cell death required for homeostasis of human tissues. Apoptotic cells display several morphological and biochemical changes, which are a consequence of the activity of caspase proteases.1 Caspases are normally inactive in the cytosol, but they become activated by dimerization and/or proteolysis by other caspases. 'Executioner' caspases such as caspase-3 are activated through cleavage by 'initiator' or 'apical' caspases, of which the best characterized are caspases-8 and -9. Caspase-8 is activated by its recruitment to the multimeric DISC (death-inducing signaling complex) in response to extracellular ligands such as Fas/CD95-ligand, TRAIL or TNF; 2 this is the death receptor, or extrinsic pathway of apoptosis. Caspase-9 is activated by dimerization after recruitment to the apoptosome, a complex of APAF1 proteins formed in response to the release of the mitochondrial protein cytochrome c into the cytosol. 3 This caspase activation cascade is called the mitochondrial or intrinsic pathway of apoptosis.The mitochondrial pathway of apoptosis is regulated by proteins of the Bcl-2 family, which regulate the integrity of the mitochondrial outer membrane, thereby controlling cytochrome c and subsequent caspase activation.4 Impairment of the mitochondrial pathway is common in human tumors. Cancer cells frequently overexpress the antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1, or they lack functional proapoptotic Bcl-2 family members, including Bax, Bak or both. 5 The overexpression of antiapoptotic Bcl-2 proteins not only blocks the morphological features of apoptosis, but also enables clonogenic cell survival. 6 For these reasons, cells from Bax, B...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells

et al. 2010

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“…The previously described human neuroblastoma cells NB7 and NB7C8 were cultured in RPMI with 10% fetal bovine serum and antibiotics (20). Lentiviral-mediated down-regulation of caspase 8 in A549 cells by short hairpin RNA was previously described (25). Stably transfected cells were maintained in presence of 400 g of puromycin.…”

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confidence: 99%

Caspase 8 Promotes Peripheral Localization and Activation of Rab5

Torres

Mielgo

Barilá

et al. 2008

Journal of Biological Chemistry

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Caspase 8 is a cysteine protease that initiates apoptotic signaling via the extrinsic pathway in a manner dependent upon association with early endosomes. Previously, we identified caspase 8 as an effector of migration, promoting motility in a manner dependent upon phosphorylation on Tyr-380 by Src family kinases and its subsequent association with Src homology 2 domain-containing proteins. Here we demonstrate the regulation of the small GTPase Rab5, which mediates early endosome formation, homotypic fusion, and maturation by caspase 8. Regulation requires the Tyr-380 phosphorylation site but not caspase proteolytic activity. Tyr-380 is essential for interaction with the Src homology 2 domains of p85␣, a multifunctional adaptor for phosphatidylinositol 3-kinase, that possesses Rab-GAP activity. Interaction between caspase 8 and p85␣ promotes Rab5 GTP loading, alters endosomal trafficking, and results in the accumulation of Rab5-positive endosomes at the edge of the cell. Conversely, caspase 8-dependent GTP loading of Rab5 is overcome by increased expression of p85␣ in a Rab-GAPdependent manner. Thus, we demonstrate a novel function for caspase 8 as a modulator of p85␣ Rab-GAP activity and endosomal trafficking.Rab5 is a small GTPase involved in clathrin-coated vesicle formation, vesicle-early endosome, and early endosome homotypic fusion as well as endosome maturation (for review, see Refs. 1 and 2). Rab5 cycling between the GDP-(inactive) and GTP-bound (active) forms is a process tightly controlled by GTPase-activating proteins (GAPs), 2 guanine nucleotide-exchange factors, and GDP dissociation inhibitors. This strict control is critical to the correct "activation" of Rab5 in time and space (1). GTP-bound Rab5 binds many effectors, including EEA1 (3), Rabaptin5 (4), Rabenosyn5 (5), and phosphatidylinositol 3-kinases (6), thus accounting for its influence on endosome tethering, fusion, and transport (2). The amount of GTP-loaded Rab5 acts as a rate-limiting step influencing the extent of endosome docking and fusion (7). Characterization of GAPs and guanine nucleotide-exchange factors continues to provide new insights on how membrane trafficking is regulated. Recently we characterized the p85␣ subunit of phosphatidylinositol 3-kinase as a Rab-GAP, binding Rab5 via its BH domain, providing a "timing" mechanism for GTP-bound Rab5 (8). Mutation in the BH domain (R274A) impairs Rab-GAP activity, altering the trafficking and degradation of tyrosine kinase receptors (9).Caspase 8 is a cysteine protease that initiates apoptotic signaling via the extrinsic pathway in a manner dependent upon association with early endosomes (10 -12). However, increasing evidence has revealed unexpected non-apoptotic functions of caspase 8, including enhancement of cell adhesion and motility (13-17). Importantly, after phosphorylation (13, 21) caspase 8 was shown to influence cell adhesion and migration via an interaction with p85␣ in a Rac-dependent manner (16).Interestingly, Rab5 was recently shown to regulate cell motility, acting in co...

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“…Somocystinamide A (ScA) stimulates apoptosis in tumor cell lines and angiogenic endothelial cells via both the intrinsic and extrinsic pathways, but the more effective mechanism is the activation of caspase 8 and the extrinsic pathways [110]. Palmitic acid shows selective toxicity via apoptosis in leukaemic cell lines [111,112].…”

Section: Compounds That Have Multiple Targets On Apoptotic Pathwaysmentioning

confidence: 99%

Targeting Cellular Proapoptotic Agents from Marine Sources

Liu

Lin

Zheng

2014

Handbook of Anticancer Drugs From Marine Origin

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Marine organisms are an important source for the discovery of anticancer agents. In recent years, an increasing number of lead compounds have been isolated and some of them possess potent apoptosis-inducing activities in cancer cells. Apoptosis is a form of programmed cell death and is a critical defense mechanism against the occurrence of cancer. There is a long list of pro-or anti-apoptotic molecules that can trigger apoptosis. Therefore, searching agents that target these proor anti-apoptotic molecules has become an important strategy for the anticancer agent developments. This review summarizes some of marine-derived agents with pro-apoptotic activities and discusses the existing challenges and our perspectives on the development of anticancer agents from marine source.

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The marine lipopeptide somocystinamide A triggers apoptosis via caspase 8

Abstract: angiogenesis ͉ cancer ͉ nanoparticle

Cited by 108 publications

References 35 publications

Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells

Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells

Caspase 8 Promotes Peripheral Localization and Activation of Rab5

Targeting Cellular Proapoptotic Agents from Marine Sources

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