@article{2a932cd4543d454983a08db7aef2f993,
title = "Sirt1–nox4 signaling axis regulates cancer cachexia",
abstract = "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.",
author = "Aneesha Dasgupta and Shukla, {Surendra K.} and Enza Vernucci and King, {Ryan J.} and Jaime Abrego and Mulder, {Scott E.} and Mullen, {Nicholas J.} and Gavin Graves and Kyla Buettner and Ravi Thakur and Divya Murthy and Attri, {Kuldeep S.} and Dezhen Wang and Chaika, {Nina V.} and Pacheco, {Camila G.} and Ibha Rai and Engle, {Dannielle D.} and Grandgenett, {Paul M.} and Michael Punsoni and Reames, {Bradley N.} and Melissa Teoh-Fitzgerald and Rebecca Oberley-Deegan and Fang Yu and Klute, {Kelsey A.} and Hollingsworth, {Michael A.} and Zimmerman, {Matthew C.} and Kamiya Mehla and Junichi Sadoshima and Tuveson, {David A.} and Singh, {Pankaj K.}",
note = "Funding Information: Disclosures: D.A. Tuveson reported {"}other{"} from Surface Oncology, Leap Therapeutics, and Cygnal Therapeutics; grants from ONO and Fibrogen; personal fees from Chugai and Merck outside the submitted work; SAB, stock from Surface Oncology, Leap Therapeutics, and Cygnal Therapeutics; sponsored research from ONO and Fibrogen; and honoraria from Chugai and Merck. No other disclosures were reported. Funding Information: This work was supported in part by funding from the National Institutes of Health National Cancer Institute (grants R01CA210439, R01CA163649, and R01CA216853 to P.K. Singh; Specialized Programs for Research Excellence grant 2P50 CA127297 to M.A. Hol-lingsworth and P.K. Singh; grant P01CA217798 to P.K. Singh and M.A. Hollingsworth; Research Specialist award 5R50CA211462 to P.M. Grandgenett; and Pancreatic Cancer Detection Consortium grant U01CA210240 to M.A. Hollingsworth). D.A. Tuveson was supported by the Lustgarten Foundation; the Cold Spring Harbor Cancer Center Support Grant Shared Resources; and National Institutes of Health grants P30CA45508, U01CA210240, R01CA188134, and R01CA190092. EPR spectroscopy data were obtained from the University of Nebraska{\textquoteright}s EPR Spectroscopy Core, which is supported, in part, by a the National Institute of General Medical Sciences (grant P30GM103335) awarded to the University of Nebraska{\textquoteright}s Redox Biology Center. We would also like to acknowledge the Fred & Pamela Buffett Cancer Center Support Grant (National Cancer Institute grant P30CA036727) for supporting shared resources. Publisher Copyright: {\textcopyright} 2020 Dasgupta et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).",
year = "2020",
month = jul,
day = "6",
doi = "10.1084/jem.20190745",
language = "English (US)",
volume = "217",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "7",
}