HuR's post-transcriptional regulation of Death Receptor 5 in pancreatic cancer cells.

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
• Jonathan R Brody

Publication/Presentation Date

8-1-2012

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.

Volume

13

Issue

10

First Page

946

Last Page

955

ISSN

1555-8576

Published In/Presented At

Pineda, D. M., Rittenhouse, D. W., Valley, C. C., Cozzitorto, J. A., Burkhart, R. A., Leiby, B., Winter, J. M., Weber, M. C., Londin, E. R., Rigoutsos, I., Yeo, C. J., Gorospe, M., Witkiewicz, A. K., Sachs, J. N., & Brody, J. R. (2012). HuR's post-transcriptional regulation of Death Receptor 5 in pancreatic cancer cells. Cancer biology & therapy, 13(10), 946–955. https://doi.org/10.4161/cbt.20952

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

22785201

Department(s)

Administration and Leadership

Document Type

Article