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Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS.

ABSTRACT: Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo-Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction.

SUBMITTER: Karekar P

PROVIDER: S-EPMC8389295 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOur previous work suggested that microtubule associated protein 4 (MAP4) phosphorylation led to mitochondrial dysfunction in MAP4 phosphorylation mutant mice with cardiomyopathy, but the detailed mechanism was still unknown. Thus, the aim of this study was to investigate the potential mechanism involved in mitochondrial dysfunction responsible for cardiomyopathy.MethodsThe present study was conducted to explore the potential mechanism underlying the mitochondrial dysfunction driven by MAP4 phosphorylation. Strain of mouse that mimicked constant MAP4 phosphorylation (S737 and S760) was generated. The isobaric tag for relative and absolute quantitation (iTRAQ) analysis was applied to the heart tissue. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) were all analyzed on the basis of differential expressed proteins (DEPs).ResultsAmong the 72 cardiac DEPs detected between the two genotypes of mice, 12 were upregulated and 60 were downregulated. GO analysis showed the biological process, molecular function, and cellular component of DEPs, and KEGG enrichment analysis linked DEPs to 96 different biochemical pathways. In addition, the PPI network was also extended on the basis of DEPs as the seed proteins. Three proteins, including mitochondrial ubiquitin ligase activator of NF-κB 1, reduced form of nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial and growth arrest, and DNA-damage-inducible proteins-interacting protein 1, which play an important role in the regulation of mitochondrial function, may correlate with MAP4 phosphorylation-induced mitochondrial dysfunction. Western blot was used to validate the expression of the three proteins, which was consistent with iTRAQ experiments.ConclusionsThese findings revealed that the DEPs caused by MAP4 phosphorylation in heart tissue using iTRAQ technique and may provide clues to uncover the potential mechanism of MAP4 phosphorylation-induced mitochondrial dysfunction.

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Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS.

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