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The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase

¹ Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Departments of ² Pathology and ³ Pharmacology and Experimental Therapeutics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; ⁴ LCMB, National Institute on Aging-Intramural Research Program, NIH, Baltimore, Maryland; and ⁵ Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Camden, New Jersey

Requests for reprints: Jonathan R. Brody, Department of Surgery, Thomas Jefferson University, 1015 Walnut Street, Curtis 611A, Philadelphia, PA 19107. Phone: 215-955-2693; E-mail: Jonathan.Brody{at}jefferson.edu.

Key Words: pancreatic ductal adenocarcinoma • pancreatic cancer • HuR • gemcitabine • deoxycytidine kinase • mRNA binding protein • gemcitabine response • RNA binding proteins

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. [Cancer Res 2009;69(11):4567–72]