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

Ferguson, Robert, Aughton, Karen ORCID: 0000-0002-5184-5789, Evans, Anthony ORCID: 0000-0001-8547-1730, Shaw, Victoria ORCID: 0000-0002-0429-0186, Armstrong, Jane, Ware, Adam, Bennett, Laura, Costello, Eithne and Greenhalf, William ORCID: 0000-0002-1865-3195 (2023) Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation. CURRENT ISSUES IN MOLECULAR BIOLOGY, 45 (3). pp. 2505-2520.

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Official URL: http://dx.doi.org/10.3390/cimb45030164

Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	pancreatic ductal adenocarcinoma, K-Ras, N-Ras, G2 cyclins
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Clinical Directorate Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User:	Symplectic Admin
Date Deposited:	18 Apr 2023 08:38
Last Modified:	19 Apr 2023 10:59
DOI:	10.3390/cimb45030164
Open Access URL:	https://doi.org/10.3390/cimb45030164
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169646