Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers.
BACKGROUND
Pancreatic cancer is the fourth leading cause of death in the US. Unlike other solid tumors such as testicular cancer which are now curable, more than 90% of pancreatic cancer patients die due to lack of response to therapy. Recently, the level of 14-3-3σ mRNA was found to be increased in pancreatic cancers and this increased expression may contribute to the failure in treatment of pancreatic cancers. In the present study, we tested this hypothesis.


METHODS
Western blot analysis was used to determine 14-3-3σ protein level in fresh frozen tissues and was correlated to clinical outcome. A stable cell line expressing 14-3-3σ was established and the effect of 14-3-3σ over-expression on cellular response to radiation and anticancer drugs were tested using SRB assay and clonogenic assays. Cell cycle distribution and apoptosis analyses were performed using propidium iodide staining and PARP cleavage assays.


RESULTS
We found that 14-3-3σ protein level was increased significantly in about 71% (17 of 24) of human pancreatic cancer tissues and that the 14-3-3σ protein level in cancers correlated with lymph node metastasis and poor prognosis. Furthermore, we demonstrated that over-expression of 14-3-3σ in a pancreatic cancer cell line caused resistance to γ-irradiation as well as anticancer drugs by causing resistance to treatment-induced apoptosis and G2/M arrest.


CONCLUSIONS
The increased level of 14-3-3σ protein likely contributes to the poor clinical outcome of human pancreatic cancers by causing resistance to radiation and anticancer drugs. Thus, 14-3-3σ may serve as a prognosis marker predicting survival of pancreatic cancer patients and guide the clinical treatment of these patients.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. jianzhan@iupui.edu.
Zhaomin
Z
Li
Zizheng
Z
Dong
David
D
Myer
Michele
M
Yip-Schneider
Jianguo
J
Liu
Ping
P
Cui
C Max
CM
Schmidt
Jian-Ting
JT
Zhang
D048948:14-3-3 Proteins / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000502:physiology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005092:Exonucleases / Q000502:physiology*; D005095:Exoribonucleases; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011379:Prognosis; D016896:Treatment Outcome
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human