The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase.

Authors

• Christina L Costantino
• Agnieszka K Witkiewicz
• Yuki Kuwano
• Joseph A Cozzitorto
• Eugene P Kennedy
• Abhijit Dasgupta
• Judith C Keen
• Charles J Yeo
• Myriam Gorospe
• Jonathan R Brody

Publication/Presentation Date

6-1-2009

Abstract

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.

Volume

69

Issue

11

First Page

4567

Last Page

4572

ISSN

1538-7445

Published In/Presented At

Costantino, C. L., Witkiewicz, A. K., Kuwano, Y., Cozzitorto, J. A., Kennedy, E. P., Dasgupta, A., Keen, J. C., Yeo, C. J., Gorospe, M., & Brody, J. R. (2009). The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer research, 69(11), 4567–4572. https://doi.org/10.1158/0008-5472.CAN-09-0371

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

19487279

Department(s)

Administration and Leadership

Document Type

Article