<i>Pseudomonas</i> Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1

Du, Xiaohong; Youle, Richard J.; FitzGerald, David J.; Pastan, Ira

doi:10.1128/mcb.00813-09

Cited by 69 publications

(74 citation statements)

References 42 publications

(53 reference statements)

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“…Du et al reported that ETA-induced cytotoxicity in MEF cells was suppressed by overexpression of Mcl-1, suggesting that ETA induces intrinsic pathway-dependent apoptosis initiated by MOMP in MEF cells (17). Conformational change in Bak was induced concurrent with loss of Mcl-1 in Cholixtreated HeLa cells (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…Cholix exhibits high structural homology to ETA, which was shown to cause caspase-3-and -8-dependent apoptosis in human mast cells (29). In ETA-treated MEF cells, MOMP-dependent apoptosis is induced (17). Unlike these reports, we found that Cholix-induced HeLa cell death involved multiple apoptotic pathways, including mitochondria-dependent and -independent apoptotic signals and that caspase-1, -4, and -5 seemed to be responsible at an early stage for caspasedependent apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Du et al reported that in mouse embryo fibroblasts (MEF) ETA inhibits synthesis of anti-apoptotic Bcl-2 family protein Mcl-1 and induces apoptosis, a process dependent on MOMP initiated by pro-apoptotic Bcl-2 family protein Bak (17). The cholix gene is present in many strains of V. cholerae independent of serogroup (7), and Cholix shows cytotoxicity in MEF cells (8).…”

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confidence: 99%

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Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells

Ogura

Yahiro

Tsutsuki

et al. 2011

Journal of Biological Chemistry

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Background: Cholix toxin (Cholix) is a novel ADP-ribosyl transferase cytotoxin produced by Vibrio cholerae. Results: Cholix-induced apoptosis is dependent on caspase activation, which is regulated by both mitochondria-dependent and -independent pathways. Conclusion: Inflammatory caspases and caspase-8 are responsible for both mitochondrial signals and other caspase activation. Significance: The cell death pathway induced by eEF2-ADP-ribosylation might differ in various cell types.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells

Ogura

Yahiro

Tsutsuki

et al. 2011

Journal of Biological Chemistry

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“…Pro-survival protein Mcl-1 is considered to preferentially restrict the activation of Bak but not Bax [37,38], whilst Bcl-2 inactivates Bax. Previous publications reported that some apoptotic stimulus induced apoptosis via a Bak-dependent pathway by accelerating the degradation of Mcl-1 [37,39,40,41].…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

et al. 2013

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Melanoma is one of the most aggressive types of skin cancer and its incidence rate is still increasing. All existing treatments are minimally effective. Consequently, new therapeutic agents for melanoma treatment should be developed. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor and antimetastatic properties. The aim of this study was to evaluate the different signaling pathways involved in the cytotoxic effect of DM-1 on melanoma cells.The apoptotic process and cytoskeletal changes were evaluated by immunoblotting and immunofluorescence, respectively, in melanoma cells.After DM-1 treatment, SK-MEL-5 melanoma cells showed actin filaments disorganization with spicules formation throughout the cytoskeleton and significant reduction of focal adhesion as well as they were present only at cell extremities, conferring a poor connection between the cell and the substrate. Besides this, there was significant filopodium retraction and loss of typical cytoskeleton scaffold. These modifications contributed to cell detachment followed by cell death.Furthermore, DM-1-induced apoptosis was triggered by multiple Bcl-2 proteins involved in both the extrinsic and the intrinsic apoptotic pathways. SK-MEL-5 cells showed a death mechanism mainly by Bcl-2/Bax ratio decrease, whereas A375 cells presented apoptosis induction by Mcl-1 and Bcl-xL downregulation. In SK-MEL-5 and A375 melanoma cells, there were a significant increase in the active form of caspase 9 and the inactive form of the effector caspase 3 was decreased in both cell lines. Expression of cleaved Parp was increased after DM-1 treatment in these melanoma cell lines, demonstrating 2 that the apoptotic process occurred. Altogether, these data elucidate the cellular and molecular mechanisms involved in the cytotoxicity induced by the antitumor agent DM-1 in melanoma cells.

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“…Immunotoxin-mediated inhibition of protein synthesis results in rapid MCL-1 depletion (40), which suggests that use of an immunotoxin as part of a combination therapy may uniquely sensitize TNBC to other treatments. Follow-up experiments testing a combination of 806-PE38 with other small molecular weight inhibitors may further enhance cell killing, as observed for combination treatments utilizing ITs targeting other cancers (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

Simon

Antignani

Sarnovsky

et al. 2016

JNCI J Natl Cancer Inst

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Background: Triple-negative breast cancers (TNBCs) are typically more aggressive and result in poorer outcomes than other breast cancers because treatment options are limited due to lack of hormone receptors or amplified human epidermal growth factor receptor 2 (HER2). Many TNBCs overexpress the epidermal growth factor receptor (EGFR) or manifest amplification of the EGFR gene, supporting EGFR as a therapeutic target. While EGFR-directed small molecule inhibitors have shown limited effectiveness in clinical settings, use of EGFR as a mechanism of delivering enzymatic cytotoxins to TNBC has not been demonstrated. Methods: Using the single-chain variable fragment (scFv) of the 806 antibody that binds only cells with overexpressed, misfolded, or mutant variants of the EGFR, a recombinant immunotoxin was engineered through gene fusion with Pseudomonas aeruginosa Exotoxin A (806-PE38). The potency of 806-PE38 on reducing TNBC cell growth in vitro and in xenograft models (n 6) was examined for six TNBC cell lines. All statistical tests were two-sided. Results: 806-PE38 statistically significantly reduced the viability of all tested TNBC lines, with IC 50 values below 10 ng/mL for three of six cell lines, while not affecting cells with wild-type EGFR (IC 50 >300 ng/mL). Systemic treatments with 806-PE38 vs vehicle resulted in statistically significantly reduced tumor burdens (806-PE38 mean ¼ 128 mm 3 [SD ¼ 46 mm 3 ] vs vehicle mean ¼ 749 mm 3 [SD ¼ 395 mm 3 ], P ¼ .001) and increased median survival (806-PE38 median ¼ 82 days vs vehicle median ¼ 50 days, P ¼ .01) in a MDA-MB-468 TNBC mouse xenograft. Deletion of the catalytic residue eliminated both cytotoxic activity in vitro and the reduction in tumor burden and survival (P ¼ .52). Conclusions: These data support the further development of the 806-PE38 immunotoxin as a therapeutic agent for the treatment of patients with EGFR-positive TNBC. Follow-up experiments with combination therapies will be attempted to achieve full remissions.

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Pseudomonas Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1

Cited by 69 publications

References 42 publications

Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells

Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells

Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

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