Authors: Danielle M. Pineda, David W. Rittenhouse, Christopher C. Valley, Joseph A. Cozzitorto, Richard A. Burkhart, Benjamin Leiby, Jordan M. Winter, Matthew C. Weber, Eric R. Londin, Isidore Rigoutsos, Charles J. Yeo, Myriam Gorospe, Agnieska K. Witkiewicz, Jonathan N. Sachs and Jonathan R. Brody
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
These authors contributed equally to this work.
David W. Rittenhouse
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
These authors contributed equally to this work.
Christopher C. Valley
Dept of Biomedical Engineering; University of Minnesota; Minneapolis, MN USA
Joseph A. Cozzitorto
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Richard A. Burkhart
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Benjamin Leiby
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Jordan M. Winter
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Matthew C. Weber
Department of Pathology, Anatomy and Cell Biology; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Eric R. Londin
Computational Medicine Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Isidore Rigoutsos
Computational Medicine Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Charles J. Yeo
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Myriam Gorospe
Laboratory of Molecular Biology and Immunology; National Institute on Aging-Intramural Research Program; National Institute of Health; Baltimore, MD USA
Agnieska K. Witkiewicz
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA; Department of Pathology, Anatomy and Cell Biology; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA
Jonathan N. Sachs
Dept of Biomedical Engineering; University of Minnesota; Minneapolis, MN USA
Jonathan R. Brody
Corresponding author: jonathan.brody@jefferson.edu
Dept. of Surgery, Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA; Laboratory of Molecular Biology and Immunology; National Institute on Aging-Intramural Research Program; National Institute of Health; Baltimore, MD USA
Abstract:
Apoptosis is one of the core signaling pathways disrupted in pancreatic ductal adenocarcinoma (PDA). Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF)-receptor superfamily that is expressed in cancer cells. Binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR5 is a potent trigger of the extrinsic apoptotic pathway, and numerous clinical trials are based on DR5-targeted therapies for cancer, including PDA. Human antigen R (HuR), an RNA-binding protein, regulates a select number of transcripts under stress conditions. Here we report that HuR translocates from the nucleus to the cytoplasm of PDA cells upon treatment with a DR5 agonist. High doses of DR5 agonist induce cleavage of both HuR and caspase 8. HuR binds to DR5 mRNA at the 5′-untranslated region (UTR) in PDA cells in response to different cancer-associated stressors and subsequently represses DR5 protein expression; silencing HuR augments DR5 protein production by enabling its translation and thus enhances apoptosis. In PDA specimens (n = 53), negative HuR cytoplasmic expression correlated with elevated DR5 expression (odds ratio 16.1, p < 0.0001). Together, these data demonstrate a feedback mechanism elicited by HuR-mediated repression of the key apoptotic membrane protein DR5.
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