HuR’s role in gemcitabine efficacy in pancreatic cancer: HuR upregulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase

摘要

RNA-binding protein HuR binds U- or AU-rich sequences in the 3′-untranslated regions (UTRs) of target mRNAs, stabilizing them and/or modulating their translation. Given HuR’s links with cancer, we studied the consequences of modulating HuR levels in pancreatic cancer cells. HuR-overexpressing cancer cells, in some instances, are up to 30-fold more sensitive to treatment with gemcitabine (GEM), the main chemotherapeutic component of treatment regimens for pancreatic ductal adenocarcinoma (PDA), compared to control cells. In pancreatic cancer cells, HuR associates with deoxycytidine kinase (dCK) mRNA, which encodes the enzyme that metabolizes and thereby activates GEM. GEM exposure to pancreatic cancer cells, enriches the association between HuR and dCK mRNA and increases cytoplasmic HuR levels. Accordingly, HuR overexpression elevates, while HuR silencing reduces, dCK protein expression in pancreatic cancer cells. In a clinical correlate study of GEM treatment, we found a 7-fold increase in risk of mortality in PDA patients with low cytoplasmic HuR levels compared to 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 GEM efficacy in cancer cells, at least in part through its ability to regulate dCK levels post-transcriptionally. We propose that HuR levels in PDA modulate the therapeutic efficacy of GEM, thus serving as a marker of the clinical utility of this common chemotherapeutic agent and a potential target for intervention in pancreatic cancer.