Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation

• Published in: Current issues in molecular biology 2023-03, Vol.45 (3), p.2505-2520
• Main Authors: Ferguson, Robert, Aughton, Karen, Evans, Anthony, Shaw, Victoria, Armstrong, Jane, Ware, Adam, Bennett, Laura, Costello, Eithne, Greenhalf, William
• Format: Article
• Language: English
• Subjects: G2 cyclins; K-Ras; N-Ras; pancreatic ductal adenocarcinoma
• ISSN: 1467-3045; 1467-3037; 1467-3045
• DOI: 10.3390/cimb45030164

The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.