WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells

• Published in: Hepatobiliary & pancreatic diseases international 2014-10, Vol.13 (5), p.529-538
• Main Authors: Wei, Wei, Sun, Hui-Hui, Li, Na, Li, Hong-Yue, Li, Xin, Li, Qiang, Shen, Xiao-Hong
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - chemistry; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Antimetabolites, Antineoplastic - pharmacology; cell cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; chemoresistance; Cyclin D - analysis; Cyclin D - genetics; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Resistance, Neoplasm - genetics; Endocrinology & Metabolism; Female; Flow Cytometry; Gastroenterology and Hepatology; Gene Knockdown Techniques; Humans; Inhibitory Concentration 50; Male; Middle Aged; Neoplasm Staging; Pancreas - chemistry; pancreatic cancer; Pancreatic Neoplasms - chemistry; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphorylation; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - analysis; Proto-Oncogene Proteins c-akt - metabolism; Retinoblastoma Protein - metabolism; RNA, Messenger - metabolism; Wnt Proteins - analysis; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt-5a Protein; WNT5A; 临床; 医学; 治疗; 肝胆疾病; 诊断
• ISSN: 1499-3872
• DOI: 10.1016/S1499-3872(14)60277-0

BACKGROUND： Although there are many studies on the mechanism of chemoresistance in cancers, studies on the relations between WNT5 A and chemoresistance in pancreatic cancer are rare. The present study was to examine the role of WNT5 A in the regulation of cell cycle progression and in chemoresistance in pancreatic cancer tissues and cell lines.METHODS： Fresh pancreatic cancer and paracarcinoma tissues were obtained from 32 patients. The expressions of WNT5 A,AKT/p-AKT and Cyclin D1 were detected by immunohistochemistry,and the correlation between WNT5 A expression and clinicopathological characteristics was analyzed. The relationship between WNT5 A expression and gemcitabine resistance was studied in PANC-1 and MIAPaCa2 cell lines. The effect of WNT5 A on the regulation of cell cycle and gemcitabine cytotoxicity were investigated. The associations among the expressions of p-AKT,Cyclin D1 and WNT5 A were also analyzed in cell lines and the effect of WNT5 A on restriction-point（R-point） progression was evaluated.RESULTS： WNT5 A, p-AKT and Cyclin D1 were highly expressed in pancreatic cancer tissues, and the WNT5 A expression was correlated with the TNM stages. In vitroWNT5 A expression was associated with gemcitabine chemoresistance. The percentage of cells was increased in G0/G1 phase and decreased in S phase after knockdown of WNT5 A in PANC-1. WNT5 A promoted Cyclin D1 expression through phosphorylation of AKT which consequently enhanced G1-S transition and gemcitabine resistance. Furthermore, WNT5 A enhanced the cell cycle progression toward R-point through regulation ofretinoblastoma protein（pRb） and pRb-E2 F complex formation.CONCLUSIONS： WNT5 A induced chemoresistance by regulation of G1-S transition in pancreatic cancer cells. WNT5 A might serve as a predictor of gemcitabine response and as a potential target for tumor chemotherapy.