Resumen
Doxorubicin (DOX) is an effective anti-cancer agent. However, DOX treatment increases patient susceptibility to dilated cardiomyopathy. DOX predisposes cardiomyocytes to insult by suppressing mitochondrial energy metabolism, altering calcium flux, and disrupting proteolysis and proteostasis. Prior studies have assessed the role of macroautophagy in DOX cardiotoxicity; however, limited studies have examined whether DOX mediates cardiac injury through dysfunctions in inter-And/or intra-lysosomal signaling events. Lysosomal signaling and function is governed by transcription factor EB (TFEB). In the present study, we hypothesized that DOX caused myocyte injury by impairing lysosomal function and signaling through negative regulation of TFEB. Indeed, we found that DOX repressed cellular TFEB expression, which was associated with impaired cathepsin proteolytic activity across in vivo, ex vivo, and in vitro models of DOX cardiotoxicity. Furthermore, we observed that loss of TFEB was associated with reduction in macroautophagy protein expression, inhibition of autophagic flux, impairments in lysosomal cathepsin B activity, and activation of cell death. Restoration and/or activation of TFEB in DOXtreated cardiomyocytes prevented DOX-induced suppression of cathepsin B activity, reduced DOX-mediated reactive oxygen species (ROS) overproduction, attenuated activation of caspase-3, and improved cellular viability. Collectively, loss of TFEB inhibits lysosomal autophagy, rendering cardiomyocytes susceptible to DOX-induced proteotoxicity and injury. Our data reveal a novel mechanism wherein DOX primes cardiomyocytes for cell death by depleting cellular TFEB.
Idioma original | English |
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Páginas (desde-hasta) | 3769-3789 |
Número de páginas | 21 |
Publicación | Biochemical Journal |
Volumen | 473 |
N.º | 21 |
DOI | |
Estado | Published - 2016 |
Nota bibliográfica
Funding Information:This work was funded by grants from the Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-03687] and the New Brunswick Health Research Foundation to T.P. and P.C.K. J.J.B. was supported by the government of New Brunswick through a New Brunswick Health Research Foundation summer studentship.
Publisher Copyright:
© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
ASJC Scopus Subject Areas
- Biochemistry
- Molecular Biology
- Cell Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't