SIRT1-NOX4 Signaling Axis Regulates Cancer Cachexia

Dasgupta, A., Shukla, S.K., Vernucci, E., King, R.J., Abrego, J., Mulder, S.E., Mullen, N.J., Graves, G., Buettner, K., Thakur, R., Murthy, D., Attri, K.S., Wang, D., Chaika, N.V., Pacheco, C.G., Rai, I., Engle, D. D., Grandgenett, P. M., Punsoni, M., Reames, B.N., Teoh-Fitzgerald, M., Oberley-Deegan, R., Yu, F., Klute, K.A., Hollingsworth, M.A., Zimmerman, M.C., Mehla, K., Sadoshima, J., Tuveson, D. A., Singh, P.K. (July 2020) SIRT1-NOX4 Signaling Axis Regulates Cancer Cachexia. J Exp Med, 217 (7). e20190745. ISSN 0022-1007

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DOI: 10.1084/jem.20190745


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-κB 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.

Item Type: Paper
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling
CSHL Authors:
Communities: CSHL Cancer Center Program
CSHL labs > Tuveson lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Adrian Gomez
Date: 6 July 2020
Date Deposited: 01 Jun 2020 13:38
Last Modified: 29 Jun 2021 15:22
PMCID: PMC7336299
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