| First Author | Dasgupta A | Year | 2020 |
| Journal | J Exp Med | Volume | 217 |
| Issue | 7 | PubMed ID | 32441762 |
| Mgi Jnum | J:302283 | Mgi Id | MGI:6457891 |
| Doi | 10.1084/jem.20190745 | Citation | Dasgupta A, et al. (2020) SIRT1-NOX4 signaling axis regulates cancer cachexia. J Exp Med 217(7) |
| abstractText | Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-kappaB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia. |
