The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase.
RNA-binding protein HuR binds U- or AU-rich sequences in the 3'-untranslated regions of target mRNAs, stabilizing them and/or modulating their translation. Given the links of HuR with cancer, we studied the consequences of modulating HuR levels in pancreatic cancer cells. HuR-overexpressing cancer cells, in some instances, are roughly up to 30-fold more sensitive to treatment with gemcitabine, the main chemotherapeutic component of treatment regimens for pancreatic ductal adenocarcinoma (PDA), compared with control cells. In pancreatic cancer cells, HuR associates with deoxycytidine kinase (dCK) mRNA, which encodes the enzyme that metabolizes and thereby activates gemcitabine. Gemcitabine exposure to pancreatic cancer cells enriches the association between HuR and dCK mRNA and increases cytoplasmic HuR levels. Accordingly, HuR overexpression elevates, whereas HuR silencing reduces, dCK protein expression in pancreatic cancer cells. In a clinical correlate study of gemcitabine treatment, we found a 7-fold increase in risk of mortality in PDA patients with low cytoplasmic HuR levels compared with patients with high HuR levels, after adjusting for other treatments and demographic variables. These data support the notion that HuR is a key mediator of gemcitabine efficacy in cancer cells, at least in part through its ability to regulate dCK levels posttranscriptionally. We propose that HuR levels in PDA modulate the therapeutic efficacy of gemcitabine, thus serving as a marker of the clinical utility of this common chemotherapeutic agent and a potential target for intervention in pancreatic cancer.
Costantino
Christina L
CL
Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Departments of Pathology and Pharmacology and Experimental Therapeutics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Witkiewicz
Agnieszka K
AK
Kuwano
Yuki
Y
Cozzitorto
Joseph A
JA
Kennedy
Eugene P
EP
Dasgupta
Abhijit
A
Keen
Judith C
JC
Yeo
Charles J
CJ
Gorospe
Myriam
M
Brody
Jonathan R
JR
D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics*; D003561:Cytarabine / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
D000954:Antigens, Surface; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016601:RNA-Binding Proteins; D003561:Cytarabine; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine