The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila

AbstractAntimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

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The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila

eLife ◽

10.7554/elife.45061 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 7

Author(s):

Jean-Philippe Parvy ◽

Yachuan Yu ◽

Anna Dostalova ◽

Shu Kondo ◽

Alina Kurjan ◽

...

Keyword(s):

Cell Death ◽

Tumour Necrosis Factor ◽

Tumour Cell ◽

Tumour Necrosis ◽

Tumour Progression ◽

Tumour Cells ◽

Tumour Regression ◽

Necrosis Factor

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

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Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury

Gut ◽

10.1136/gutjnl-2019-318215 ◽

2019 ◽

Vol 69 (1) ◽

pp. 133-145 ◽

Cited By ~ 3

Author(s):

Yuan Zhuang ◽

Haifeng C Xu ◽

Prashant V Shinde ◽

Jens Warfsmann ◽

Jelena Vasilevska ◽

...

Keyword(s):

Cell Death ◽

Mental Retardation ◽

Liver Disease ◽

Tumour Necrosis Factor ◽

Liver Damage ◽

Tumour Necrosis ◽

Fragile X ◽

Fragile X Mental Retardation ◽

Necrosis Factor

ObjectiveThe Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease.DesignMice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry.ResultsFmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL.ConclusionsWe show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.

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Decision letter: The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila

10.7554/elife.45061.018 ◽

2019 ◽

Author(s):

Georg Halder

Keyword(s):

Cell Death ◽

Antimicrobial Peptide ◽

Tumour Necrosis Factor ◽

Tumour Cell ◽

Tumour Necrosis ◽

Necrosis Factor ◽

Tumour Cell Death

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Faculty Opinions recommendation of The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736292589.793563730 ◽

2019 ◽

Author(s):

Jean-Luc Imler

Keyword(s):

Cell Death ◽

Antimicrobial Peptide ◽

Tumour Necrosis Factor ◽

Tumour Cell ◽

Tumour Necrosis ◽

Necrosis Factor ◽

Tumour Cell Death

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Faculty Opinions recommendation of The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736292589.793563514 ◽

2019 ◽

Author(s):

Dominique Ferrandon

Keyword(s):

Cell Death ◽

Antimicrobial Peptide ◽

Tumour Necrosis Factor ◽

Tumour Cell ◽

Tumour Necrosis ◽

Necrosis Factor ◽

Tumour Cell Death

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Glutathione and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor in vivo

Biochemical Journal ◽

10.1042/bj3250183 ◽

1997 ◽

Vol 325 (1) ◽

pp. 183-189 ◽

Cited By ~ 53

Author(s):

Elena OBRADOR ◽

José NAVARRO ◽

Juan MOMPO ◽

Miguel ASENSI ◽

José A. PELLICER ◽

...

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Cell ◽

Tumour Necrosis ◽

Tumour Growth ◽

Cellular Proliferation ◽

Cell Number ◽

Slight Reduction ◽

Enhanced Sensitivity ◽

Necrosis Factor

Low rates of cellular proliferation are associated with low GSH content and enhanced sensitivity of Ehrlich ascites-tumour (EAT) cells to the cytotoxic effects of recombinant human tumour necrosis factor (rhTNF-α). Buthionine sulphoximine, a selective inhibitor of GSH synthesis, inhibited tumour growth and increased rhTNF-α cytoxicityin vitro. Administration of sublethal doses (106 units/kg per day) of rhTNF-α to EAT-bearing mice promoted oxidative stress (as measured by increases in intracellular peroxide levels, O2-• generation and mitochondrial GSSG) and resulted in a slight reduction (19%) in tumour cell number when controls showed the highest rate of cellular proliferation. ATP (1 mmol/kg per day)-induced selective GSH depletion, when combined with rhTNF-α administration, afforded a 61% inhibition of tumour growth and resulted in a significant extension of host survival. Administration of N-acetylcysteine (1 mmol/kg per day) or GSH ester (5 mmol/kg per day) abolished the rhTNF-α- and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. Our results demonstrate that the sensitivity of tumour cells to rhTNF-αin vivo depends on their GSH content and their rate of proliferation.

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