title: Tumor suppressor p16INK4a controls oncogenic K-Ras function in human pancreatic cancer cells.
abstract: Pancreatic cancer is characterized by oncogenic activation of K-Ras and inactivation of the cell cycle inhibitor p16(INK4a) . We previously demonstrated that reintroduction of p16(INK4a) reversed anoikis resistance and clonogenicity of human pancreatic cancer cells, properties commonly attributed to the transforming potential of oncogenic K-Ras. Therefore, we aimed to determine the role of Ras after p16(INK4a) re-expression. Here, we show that restitution of p16(INK4a) in pancreatic cancer cell lines elicits a profound suppression of K-Ras activity. A more detailed analysis in p16(INK4a) reconstituted Capan-1 cells indicated selective reduction of both K-Ras activity and protein stability. Re-expression of K-Ras in p16(INK4a) restituted Capan-1 cells reversed the anoikis-sensitive phenotype and increased colony formation, indicating that K-Ras suppression was required for p16(INK4a) -mediated reversion of the transformed phenotype. Inducible expression of p16(INK4a) in DanG cells confirmed inhibition of K-Ras activity as well as an increase in anoikis susceptibility. Thus, our results delineate a novel functional interaction with defined biological consequences for the two most frequent alterations observed in pancreatic cancer.
authors: Division of Gastroenterology, Department of Internal Medicine, Charité- Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany. anja.rabien@charite.de
authors: Anja
authors: A
authors: Rabien
authors: Hugo
authors: H
authors: Sanchez-Ruderisch
authors: Petra
authors: P
authors: Schulz
authors: Noreen
authors: N
authors: Otto
authors: Anja
authors: A
authors: Wimmel
authors: Bertram
authors: B
authors: Wiedenmann
authors: Katharina M
authors: KM
authors: Detjen
mesh_terms: D023102:Anoikis / Q000235:genetics; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015689:Oncogene Protein p21(ras)