HuR's post-transcriptional regulation of death receptor 5 in pancreatic cancer cells

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

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)946-955
Number of pages10
JournalCancer Biology and Therapy
Volume13
Issue number10
DOIs
StatePublished - Aug 1 2012

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Keywords

  • Apoptosis
  • DR5
  • Pancreatic cancer
  • Pancreatic ductal adenocarcinoma
  • Post-transcriptional regulation
  • TRAIL
  • TRAIL-resistance
  • TRAILR2

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

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 and Therapy, 13(10), 946-955. https://doi.org/10.4161/cbt.20952