SIRT1-NOX4 signaling axis regulates cancer cachexia

被引：61

作者：

Dasgupta, Aneesha ^{[1
]}

Shukla, Surendra K. ^{[2
]}

Vernucci, Enza ^{[2
]}

King, Ryan J. ^{[2
]}

Abrego, Jaime ^{[2
]}

Mulder, Scott E. ^{[1
]}

Mullen, Nicholas J. ^{[2
]}

Graves, Gavin ^{[2
]}

Buettner, Kyla ^{[2
]}

Thakur, Ravi ^{[2
]}

Murthy, Divya ^{[2
]}

Attri, Kuldeep S. ^{[2
]}

Wang, Dezhen ^{[2
]}

Chaika, Nina, V ^{[2
]}

Pacheco, Camila G. ^{[2
]}

Rai, Ibha ^{[2
]}

Engle, Dannielle D. ^{[3
]}

Grandgenett, Paul M. ^{[2
]}

Punsoni, Michael ^{[4
]}

Reames, Bradley N. ^{[5
]}

Teoh-Fitzgerald, Melissa ^{[1
]}

Oberley-Deegan, Rebecca ^{[1
]}

Yu, Fang ^{[6
]}

Klute, Kelsey A. ^{[7
]}

Hollingsworth, Michael A. ^{[2
]}

Zimmerman, Matthew C. ^{[8
]}

Mehla, Kamiya ^{[2
]}

Sadoshima, Junichi ^{[9
]}

Tuveson, David A. ^{[3
]}

Singh, Pankaj K. ^{[1
,2
,4
]}

机构：

[1] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA

[2] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[3] Cold Spring Harbor Lab, Canc Ctr, POB 100, Cold Spring Harbor, NY 11724 USA

[4] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA

[5] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA

[6] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE USA

[7] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA

[8] Univ Nebraska Med Ctr, Dept Cellular & Integrat Physiol, Omaha, NE USA

[9] Rutgers State Univ, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2020年 / 217卷 / 07期

基金：

美国国家卫生研究院;

关键词：

UBIQUITIN-PROTEASOME PATHWAY; NADPH OXIDASE 4; FACTOR-KAPPA-B; SKELETAL-MUSCLE; PANCREATIC-CANCER; OXIDATIVE STRESS; ACTIVATING SIRT1; MURINE MODEL; WEIGHT-LOSS; TGF-BETA;

D O I：

10.1084/jem.20190745

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B 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.

引用

页数：24

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