Sirt1–nox4 signaling axis regulates cancer cachexia

Aneesha Dasgupta, Surendra K. Shukla, Enza Vernucci, Ryan J. King, Jaime Abrego, Scott E. Mulder, Nicholas J. Mullen, Gavin Graves, Kyla Buettner, Ravi Thakur, Divya Murthy, Kuldeep S. Attri, Dezhen Wang, Nina V. Chaika, Camila G. Pacheco, Ibha Rai, Dannielle D. Engle, Paul M. Grandgenett, Michael Punsoni, Bradley N. ReamesMelissa Teoh-Fitzgerald, Rebecca Oberley-Deegan, Fang Yu, Kelsey A. Klute, Michael A. Hollingsworth, Matthew C. Zimmerman, Kamiya Mehla, Junichi Sadoshima, David A. Tuveson, Pankaj K. Singh

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish (US)
Article numbere20190745
JournalJournal of Experimental Medicine
Issue number7
StatePublished - Jul 6 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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