Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma

Sih-han Wang; Sean M Martin; Peter S Harris; C Michael Knudson

doi:10.1371/journal.pone.0019786

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Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma

Journal article

Open access

Peer reviewed

Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma

Sih-han Wang, Sean M Martin, Peter S Harris and C Michael Knudson

PloS one, Vol.6(5), pp.e19786-e19786

2011

DOI: 10.1371/journal.pone.0019786

PMCID: PMC3096637

PMID: 21611191

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Abstract

Caspase-9 is a component of the apoptosome that mediates cell death following release of cytochrome c from mitochondria. Inhibition of Caspase-9 with a dominant negative construct (Casp9DN) blocks apoptosome function, promotes viability and has been implicated in carcinogenesis. Inhibition of the apoptosome in vitro impairs mitochondrial function and promotes mitophagy. To examine whether inhibition of the apoptosome would enhance mitophagy and promote oncogenesis in vivo, transgenic mice were generated that express Casp9DN in the T cell lineage. The effects of Casp9DN on thymocyte viability, mitophagy and thymic tumor formation were examined. In primary thymocytes, Casp9DN delayed dexamethasone (Dex)-induced cell death, altered mitochondrial structure, and decreased oxidant production. Transmission electron microscopy (TEM) revealed that inhibition of the apoptosome resulted in structurally abnormal mitochondria that in some cases were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitochondria being engulfed by autophagosomes (mitophagy), confocal microscopy showed colocalization of LC3-GFP and mitochondria. However, Casp9DN did not significantly accelerate T-cell lymphoma alone, or in combination with Lck-Bax38/1, or with Beclin 1+/- mice, two tumor-prone strains in which altered mitochondrial function has been implicated in promoting tumor development. In addition, heterozygous disruption of Beclin 1 had no effect on T-cell lymphoma formation in Lck-Bax38/1 mice. Further studies showed that Beclin 1 levels had no effect on Casp9DN-induced loss of mitochondrial function. These results demonstrate that neither inhibition of apoptosome function nor Beclin 1 haploinsufficiency accelerate T-cell lymphoma development in mice.

Beclin-1

Gene Dosage - genetics

Haploinsufficiency - genetics

Reactive Oxygen Species - metabolism

Cell Separation

Cells, Cultured

bcl-2-Associated X Protein - metabolism

Mice, Transgenic

Mitochondria - drug effects

Mitochondria - pathology

Caspase Inhibitors

Mitochondria - ultrastructure

Autophagy - drug effects

Animals

Caspases - metabolism

Dexamethasone - pharmacology

Lymphoma, T-Cell - enzymology

Genes, Dominant

Lymphoma, T-Cell - pathology

Thymus Gland - pathology

Apoptosis Regulatory Proteins - genetics

Cell Proliferation - drug effects

Mice

Cell Death - drug effects

Details

Title: Subtitle: Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma
Creators: Sih-han Wang - Department of Pathology, Roy J. and Lucille P. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Sean M Martin
Peter S Harris
C Michael Knudson
Resource Type: Journal article
Publication Details: PloS one, Vol.6(5), pp.e19786-e19786
DOI: 10.1371/journal.pone.0019786
PMID: 21611191
PMCID: PMC3096637
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 CA104695 / NCI NIH HHS
Language: English
Date published: 2011
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984047629602771

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