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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.
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页码:2505 / 2520
页数:16
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