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14-3-3 Modulates Pancreatic Cancer Cell Survival and Invasiveness

Authors' Affiliation: Departments of Medicine and Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, Hanover, New Hamsphire

Requests for reprints: Murray Korc, Departments of Medicine and Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-650-7936; Fax: 603-650-6122; E-mail: murray.korc{at}dartmouth.edu.

Purpose: The purpose of the present study was to investigate the potential role of 14-3-3 in pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: 14-3-3 isoform expression was determined by real-time quantitative PCR in laser capture normal pancreatic ductal cells and pancreatic cancer cells and in 5 pancreatic cancer cell lines. PANC-1 cells, with low levels of 14-3-3, were stably transfected with a human 14-3-3 cDNA. Conversely, high endogenous 14-3-3 levels in T3M4 cells were suppressed by specific short hairpin RNA. Apoptosis, motility, and invasiveness were studied.

Results: The cancer cells in 7 PDAC samples expressed high levels of 14-3-3 mRNA by quantitative PCR when compared with normal pancreatic duct cells. 14-3-3 protein levels were high in BxPC3, COLO-357, and T3M4 cells, intermediate in ASPC-1 cells, and low in PANC-1 cells. Most cell lines released detectable amount of 14-3-3 into conditioned medium. Overexpression of 14-3-3 in PANC-1 cells led to resistance to cisplatinum-induced apoptosis, increased basal migration, and increased invasion in response to epidermal growth factor and insulin-like growth factor-I. By contrast, short hairpin RNA-mediated knockdown of endogenous 14-3-3 in T3M4 cells did not alter migration but led to enhanced cisplatinum sensitivity, increased invasiveness in response to epidermal growth factor, and decreased invasiveness in response to insulin-like growth factor-I.

Conclusions: 14-3-3 contributes to the chemoresistance of pancreatic cancer cells and exerts cell type-dependent effects on cell migration and invasion. Therefore, strategies aimed at suppressing 14-3-3 expression and function may have a therapeutic benefit in subgroups of patients with PDAC.