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

Cancer Biol Ther. 2012 Aug;13(10):946-55. doi: 10.4161/cbt.20952. Epub 2012 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Antimetabolites, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • ELAV Proteins / genetics
  • ELAV Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism*
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • RNA Processing, Post-Transcriptional*
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • 5' Untranslated Regions
  • Antimetabolites, Antineoplastic
  • ELAV Proteins
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Deoxycytidine
  • gemcitabine