• Open Access

Tumor suppressor p16INK4a controls oncogenic K-Ras function in human pancreatic cancer cells

Authors

  • Anja Rabien,

    Corresponding author
      To whom correspondence should be addressed.
      E-mail: anja.rabien@charite.de
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    • Present address: Department of Urology, Charité– Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany.

  • Hugo Sanchez-Ruderisch,

    1. Division of Gastroenterology, Department of Internal Medicine, Charité– Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Petra Schulz,

    1. Division of Gastroenterology, Department of Internal Medicine, Charité– Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Noreen Otto,

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    • Present address: Institute of Cell and Molecular Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

  • Anja Wimmel,

    1. Division of Gastroenterology, Department of Internal Medicine, Charité– Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Bertram Wiedenmann,

    1. Division of Gastroenterology, Department of Internal Medicine, Charité– Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Katharina M. Detjen

    1. Division of Gastroenterology, Department of Internal Medicine, Charité– Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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To whom correspondence should be addressed.
E-mail: anja.rabien@charite.de

Abstract

Pancreatic cancer is characterized by oncogenic activation of K-Ras and inactivation of the cell cycle inhibitor p16INK4a. We previously demonstrated that reintroduction of p16INK4a 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 p16INK4a re-expression. Here, we show that restitution of p16INK4a in pancreatic cancer cell lines elicits a profound suppression of K-Ras activity. A more detailed analysis in p16INK4a reconstituted Capan-1 cells indicated selective reduction of both K-Ras activity and protein stability. Re-expression of K-Ras in p16INK4a restituted Capan-1 cells reversed the anoikis-sensitive phenotype and increased colony formation, indicating that K-Ras suppression was required for p16INK4a-mediated reversion of the transformed phenotype. Inducible expression of p16INK4a 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. (Cancer Sci 2012; 103: 169–175)

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