BACKGROUND: Inadequate or inappropriate cell-substrate contact triggers a subset of apoptotic cell death, termed anoikis. Resistance to anoikis is a characteristic of malignant cells that is associated with increased tumorigenesis and metastasis. Focal adhesion kinase (FAK) is an important regulator of cell survival and migration and cell cycle progression. We tested the hypothesis that FAK gene silencing would promote anoikis and reverse acquired anoikis resistance in human pancreatic adenocarcinoma cells. METHODS: FAK expression was assessed by Northern and Western blot analysis. Anoikis was induced in PANC1, BxPC3, MiaPaCa2, and Mia(AR) (an anoikis-resistant derivative of MiaPaCa2) with the use of polyHEMA culture. FAK expression was suppressed by RNA interference. Anoikis was detected by YO-PRO-1/propidium iodide staining and flow cytometry. Fluorometric caspase profiling was performed. Metastasis was assayed in a nude mouse orthotopic xenograft model. RESULTS: The cell lines that were tested showed marked variation in their anoikis resistance, greater resistance being associated with higher levels of FAK expression. FAK gene silencing promoted anoikis in all cell lines and reversed acquired anoikis resistance in Mia(AR), which was associated with increased caspase activation. Suppression of FAK expression also inhibited metastasis in the nude mouse model. CONCLUSION: FAK gene silencing suppresses anoikis resistance in pancreatic adenocarcinoma cells. FAK represents a potential target for novel antimetastatic therapies.
BACKGROUND: Inadequate or inappropriate cell-substrate contact triggers a subset of apoptotic cell death, termed anoikis. Resistance to anoikis is a characteristic of malignant cells that is associated with increased tumorigenesis and metastasis. Focal adhesion kinase (FAK) is an important regulator of cell survival and migration and cell cycle progression. We tested the hypothesis that FAK gene silencing would promote anoikis and reverse acquired anoikis resistance in humanpancreatic adenocarcinoma cells. METHODS:FAK expression was assessed by Northern and Western blot analysis. Anoikis was induced in PANC1, BxPC3, MiaPaCa2, and Mia(AR) (an anoikis-resistant derivative of MiaPaCa2) with the use of polyHEMA culture. FAK expression was suppressed by RNA interference. Anoikis was detected by YO-PRO-1/propidium iodide staining and flow cytometry. Fluorometric caspase profiling was performed. Metastasis was assayed in a nude mouse orthotopic xenograft model. RESULTS: The cell lines that were tested showed marked variation in their anoikis resistance, greater resistance being associated with higher levels of FAK expression. FAK gene silencing promoted anoikis in all cell lines and reversed acquired anoikis resistance in Mia(AR), which was associated with increased caspase activation. Suppression of FAK expression also inhibited metastasis in the nude mouse model. CONCLUSION:FAK gene silencing suppresses anoikis resistance in pancreatic adenocarcinoma cells. FAK represents a potential target for novel antimetastatic therapies.
Authors: Yuen-Keng Ng; Elaine Yue Ling Wong; Cecilia Pik Yuk Lau; Jessica Pui Lan Chan; Sze Chuen Cesar Wong; Andrew Sai-Kit Chan; Maggie Pui Chun Kwan; Sai-Wah Tsao; Chi-Man Tsang; Paul Bo San Lai; Anthony Tak Cheung Chan; Vivian Wai Yan Lui Journal: Invest New Drugs Date: 2010-08-07 Impact factor: 3.850
Authors: Jyotsnabaran Halder; Charles N Landen; Susan K Lutgendorf; Yang Li; Nicholas B Jennings; Dominic Fan; Gina M Nelkin; Rosemarie Schmandt; Michael D Schaller; Anil K Sood Journal: Clin Cancer Res Date: 2005-12-15 Impact factor: 12.531
Authors: Priyanka N Gogate; Elena V Kurenova; Manivannan Ethirajan; Jianqun Liao; Michael Yemma; Arindam Sen; Ravindra K Pandey; William G Cance Journal: Cancer Lett Date: 2014-07-24 Impact factor: 8.679