Open AccessTumor suppressor p16 INK4a controls oncogenic K‐Ras function in human pancreatic cancer cells
Author(s) -
Rabien Anja,
SanchezRuderisch Hugo,
Schulz Petra,
Otto Noreen,
Wimmel Anja,
Wiedenmann Bertram,
Detjen Katharina M.
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02140.x
Subject(s) - anoikis , pancreatic cancer , cancer research , cancer cell , cancer , suppressor , cell culture , reversion , biology , cell growth , cell cycle , phenotype , chemistry , genetics , gene
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. ( Cancer Sci 2012; 103: 169–175)