Tumor suppressor p16^INK4a 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 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 p16 INK4arestituted 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)

Pre-Invasive Ovarian Mucinous Tumors Are Characterized by CDKN2A and RAS Pathway Aberrations

“…When p16 is actively expressed KRAS activity is downregulated and ERK is not phosphorylated, therefore p-ERK status is dependent on and correlates with p16 status, even in the presence of an activitating KRAS mutation. These data reiterate in ovarian tissues the findings of Rabien and colleagues (56) in pancreatic and colon cancer cells.…”

“…This study also identified a clear inverse relationship between p-ERK and p16 staining (P ¼ 0.0007, Fisher's Exact Test; Table 4) and a high level of overlap between activating KRAS mutations and p16 loss. Both the lack of correlation between KRAS mutation status and ERK phosphorylation, and the inverse relationship between p-ERK and p16 status can be explained by the negative regulation of KRAS expression and activity by p16 (56). When p16 is actively expressed KRAS activity is downregulated and ERK is not phosphorylated, therefore p-ERK status is dependent on and correlates with p16 status, even in the presence of an activitating KRAS mutation.…”

The Role of Cellular Senescence in the Gastrointestinal Mucosa

“…Pancreatic adenocarcinomas arise from premalignant pancreatic intraepithelial neoplasia 39. Progression from pancreatic intraepithelial neoplasia to adenocarcinoma results in loss of p16INK4a and thus impaired ability to form senescent cells 40. Carrière et al21 assessed the degree of senescence in pancreatic intraepithelial neoplasia and adenocarcinoma in an activated oncogenic +Kras/-RB mouse model.…”

Expression Analysis of MiR-21, MiR-205, and MiR-342 in Breast Cancer in Iran

“…About 5-10% of breast cancers are inherited, one-third of which are caused by dominant BRCA-gene mutations (Xu et al, 2011). Research has previously focused on the protein-coding genes such as oncogenes, tumor suppressor genes, DNA repair genes, and anti-metastatic genes in cancer genetics (Jacob & Praz , 2002;Rabien et al, 2011).…”