Authors

Timothy K Williams, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Christina L Costantino, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Nikolai A Bildzukewicz, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Nathan G Richards, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
David W Rittenhouse, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Lisa Einstein, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Joseph A Cozzitorto, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Judith C Keen, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Camden, New Jersey
Abhijit Dasgupta, Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Myriam Gorospe, Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland
Gregory E Gonye, Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania
Charles J Yeo, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Agnieszka K Witkiewicz, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Jonathan R Brody, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Document Type

Article

Publication Date

11-1-2010

Comments

This article has been peer reviewed and is published in PLoS One 2010, 5(11). The published version is available at DOI: 10.1371/journal.pone.0015455. © Public Library of Science

Abstract

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

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