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

被引:2
|
作者
Ferguson, Robert [1 ]
Aughton, Karen [1 ]
Evans, Anthony [1 ]
Shaw, Victoria [1 ]
Armstrong, Jane [1 ]
Ware, Adam [1 ]
Bennett, Laura [1 ]
Costello, Eithne [1 ]
Greenhalf, William [1 ]
机构
[1] Univ Liverpool, Liverpool Expt Canc Med Ctr, Liverpool L3 5TR, England
关键词
pancreatic ductal adenocarcinoma; K-Ras; N-Ras; G2; cyclins; DUCTAL ADENOCARCINORNA; EGF RECEPTOR; KRAS; MUTATIONS; GENE; ADDICTION; EMT; D1;
D O I
10.3390/cimb45030164
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2505 / 2520
页数:16
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