HuR's post-transcriptional regulation of Death Receptor 5 in pancreatic cancer cells.
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.
Department of Surgery, Division of Surgical Research, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Danielle M
DM
Pineda
David W
DW
Rittenhouse
Christopher C
CC
Valley
Joseph A
JA
Cozzitorto
Richard A
RA
Burkhart
Benjamin
B
Leiby
Jordan M
JM
Winter
Matthew C
MC
Weber
Eric R
ER
Londin
Isidore
I
Rigoutsos
Charles J
CJ
Yeo
Myriam
M
Gorospe
Agnieska K
AK
Witkiewicz
Jonathan N
JN
Sachs
Jonathan R
JR
Brody
D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D051959:ELAV Proteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003841:Deoxycytidine; D000093542:Gemcitabine