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WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death.

ABSTRACT: The anthracycline antibiotic doxorubicin (DOX) is a potent cancer chemotherapeutic agent that exerts both acute and chronic cardiotoxicity. Here we show that in adult mouse cardiomyocytes, DOX activates (i) the pro-apoptotic p53, (ii) p38MAPK and JNK, (iii) Bax translocation, (iv) cytochrome c release, and (v) caspase 3. Further, it (vi) inhibits expression of anti-apoptotic Akt, Bcl-2 and Bcl-xL, and (vii) induces internucleosomal degradation and cell death. WNT1-inducible signaling pathway protein-1 (WISP1), a CCN family member and a matricellular protein, inhibits DOX-mediated cardiomyocyte death. WISP1 inhibits DOX-induced p53 activation, p38 MAPK and JNK phosphorylation, Bax translocation to mitochondria, and cytochrome c release into cytoplasm. Additionally, WISP1 reverses DOX-induced suppression of Bcl-2 and Bcl-xL expression and Akt inhibition. The pro-survival effects of WISP1 were recapitulated by the forced expression of mutant p53, wild-type Bcl-2, wild-type Bcl-xL, or constitutively active Akt prior to DOX treatment. WISP1 also induces the pro-survival factor Survivin via PI3K/Akt signaling. Overexpression of wild-type, but not mutant Survivin, blunts DOX cytotoxicity. Further, WISP1 stimulates PI3K-Akt-dependent GSK3beta phosphorylation and beta-catenin nuclear translocation. Importantly, WISP1 induces its own expression. Together, these results provide important insights into the cytoprotective effects of WISP1 in cardiomyocytes, and suggest a potential therapeutic role for WISP1 in DOX-induced cardiotoxicity.

SUBMITTER: Venkatesan B

PROVIDER: S-EPMC2885703 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death.

Venkatesan Balachandar B Prabhu Sumanth D SD Venkatachalam Kaliyamurthi K Mummidi Srinivas S Valente Anthony J AJ Clark Robert A RA Delafontaine Patrice P Chandrasekar Bysani B

Cellular signalling 20100113 5

The anthracycline antibiotic doxorubicin (DOX) is a potent cancer chemotherapeutic agent that exerts both acute and chronic cardiotoxicity. Here we show that in adult mouse cardiomyocytes, DOX activates (i) the pro-apoptotic p53, (ii) p38MAPK and JNK, (iii) Bax translocation, (iv) cytochrome c release, and (v) caspase 3. Further, it (vi) inhibits expression of anti-apoptotic Akt, Bcl-2 and Bcl-xL, and (vii) induces internucleosomal degradation and cell death. WNT1-inducible signaling pathway pro ...[more]

PMID: 20074638

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Project description:Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox-treated H9c2 cardiac myoblast cells expressing either the mitochondria-targeted fluorescent protein MitoDsRed or the novel dual-fluorescent mitophagy reporter mt-Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA-mediated knockdown of dynamin-related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide-positive cells and the cleavage of caspase-3 and poly (ADP-ribose) polymerase. Moreover, DRP1-deficient mice were protected from Dox-induced cardiac damage, strongly supporting a role for DRP1-dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt-Rosella, suggesting the necessity of mitochondrial fragmentation in Dox-induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox-induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity.-Catanzaro, M. P., Weiner, A., Kaminaris, A., Li, C., Cai, F., Zhao, F., Kobayashi, S., Kobayashi, T., Huang, Y., Sesaki, H., Liang, Q. Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy.

Project description:The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various microenvironments encountered during a host infection. For example, the fungus-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals under alkaline conditions, highlighting the impact of microenvironmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis.IMPORTANCE The work described here further elucidates how microorganisms sense and adapt to changes in their environment to establish infections in the human host. Specifically, we uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung. This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. Furthermore, this ergosterol-dependent alkaline pH response is present in Candida albicans, indicating that this mechanism spans diverse fungal species. These results are also relevant for novel antimicrobial drug development as we show that currently used ergosterol-targeting antifungals are more active in alkaline environments.

Dataset Information

WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death.

Publications

WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death.

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