Gliotoxin – bane or boon?

Scharf, Daniel H.; Brakhage, Axel A.; Mukherjee, Prasun K.

doi:10.1111/1462-2920.13080

Cited by 104 publications

(98 citation statements)

References 143 publications

(169 reference statements)

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“…GT contains an intramolecular disulphide bond essential for its cytotoxic activity 28 . It may therefore covalently modify cysteine residues in integrin α and β chains, which are critical for integrin activation and/or their binding to extracellular matrix components 41,42 .…”

Section: Resultsmentioning

confidence: 99%

“…The breakage of the epithelial barrier is the most likely cause for the invasive property of A. fumigatus . Accumulating evidence suggests a crucial role of the major virulence factor gliotoxin (GT) in this process because fungi lacking GT production are much less virulent than wild-type (WT) strains 28 . We previously showed that GT induces a rapid detachment of human lung epithelial cells and mouse fibroblasts before they undergo caspase-dependent apoptosis 29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

et al. 2018

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Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in suspension or lacking integrin surface expression are insensitive to GT but are sensitised to ROCK-MKK4/MKK7-JNK-dependent anoikis upon attachment to fibronectin or integrin upregulation. The same signalling pathway is triggered by FAK inhibition or inhibiting integrin αV/β3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

et al. 2018

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“…Since gliotoxin may have a wide range of downstream targets (Scharf et al, 2016) and may exert its apoptotic effect via reactive oxygen species (ROS) production and via inhibition of the redox sensitive transcription factor NFκB (Gardiner et al, 2005), we evaluated the effect of gliotoxin on the nuclear expression of the NFκB subunit p65 (RelA) (Gloire and Piette, 2009). As shown in Figure 1D , gliotoxin had no influence on the expression of p65 in nuclear extracts of both cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we tested human cell lines derived from melanoma, HCC, and pancreas-CA for their nuclear NOTCH activity by EMSA and evaluated their sensitivity to the representative GSI DAPT and to the Aspergillum derived canonical NOTCH2/CSL transactivation inhibitor gliotoxin which efficiently induced apoptosis in CLL cells (Hubmann et al, 2013). The secondary metabolite gliotoxin was identified as major virulence factor in Aspergillosis patients with immunosuppressive functions and since the discovery of its structure in 1958 (Bell et al, 1958), it became a target for extensive investigations to explore its complex mechanism of action and its multiple downstream effector molecules and for potential drug development (Gardiner et al, 2005; Dolan et al, 2015; Scharf et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model

et al. 2017

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Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm3 vs. 115 mm3, p = 0.008) as well as in late stage (218 mm3 vs. 576 mm3, p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of gliotoxin in human neoplasias and gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management.

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“…A. fumigatus infection causes aspergillosis and immunosuppression (Scharf et al, 2016). The secondary metabolites produced by Aspergillus are considered to be important virulence factors.…”

Section: Introductionmentioning

confidence: 99%

Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

Zhang

Santos

et al. 2018

Cell Chemical Biology

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The 26S proteasome is the major proteolytic machine for breaking down cytosolic and nuclear proteins in eukaryotes. Due to the lack of a suitable assay, it is difficult to measure routinely and quantitatively the breakdown of proteins by the 26S proteasome in vitro. In the present study, we developed an assay to monitor proteasome-mediated protein degradation. Using this assay, we discovered that epidithiodiketopiperazine (ETPs) blocked the degradation of our model substrate in vitro. Further characterization revealed that ETPs inhibited proteasome function by targeting the essential proteasomal deubiquitinase Rpn11 (POH1/PSMD14). ETPs also inhibited other JAMM (JAB1/MPN/Mov34 metalloenzyme) proteases such as Csn5 and AMSH. An improved ETP with fewer non-specific effects, SOP11, stabilized a subset of proteasome substrates in cells, induced the unfolded protein response, and led to cell death. SOP11 represents a class of Rpn11 inhibitor and provides an alternative route to develop proteasome inhibitors.

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Gliotoxin – bane or boon?

Cited by 104 publications

References 143 publications

Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model

Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

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