PreprintArticleVersion 2Preserved in Portico This version is not peer-reviewed
Wild-type N-Ras Complements Mutant K-Ras in Pancreatic Cancer Cell Lines but K-Ras has a Specific Role in Cell Cycle Independent Regulation of G2 Cyclins
Version 1
: Received: 18 October 2022 / Approved: 20 October 2022 / Online: 20 October 2022 (04:29:55 CEST)
Version 2
: Received: 14 February 2023 / Approved: 16 February 2023 / Online: 16 February 2023 (03:22:47 CET)
Ferguson, R.; Aughton, K.; Evans, A.; Shaw, V.; Armstrong, J.; Ware, A.; Bennett, L.; Costello, E.; Greenhalf, W. Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation. Curr. Issues Mol. Biol.2023, 45, 2505-2520.
Ferguson, R.; Aughton, K.; Evans, A.; Shaw, V.; Armstrong, J.; Ware, A.; Bennett, L.; Costello, E.; Greenhalf, W. Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation. Curr. Issues Mol. Biol. 2023, 45, 2505-2520.
Abstract
Development of K-Ras independence may explain 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. 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 G2 phase to slow relative to completion of S-phase, suggesting mutant K-Ras may inhibit APC/c prior to anaphase but stabilizes 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 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. Keywords: Pancreatic Ductal Adenocarcinoma, K-Ras, N-Ras, G2 cyclins.
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
