Early Elevations of Ras Protein Level and Activity Are Critical for the Development of Pdac in the Context of Inflammation

Authors

Jianjia Ma
Fanghua Gong
Eunice Kim
James Xianxing Du
Cindy Leung
Qingchun Song
Craig D Logsdon
Yongde Luo
Xiaokun Li
Weiqin Lu

Publication Date

4-1-2024

Journal

Cancer Letters

DOI

10.1016/j.canlet.2024.216694

PMID

38307409

PMCID

PMC11032208

PubMedCentral® Posted Date

4-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly elevated both the protein level and activity of KRASG12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRASG12D and NRAS) in the early stage. Notably, while KRASG12D could be further activated by IKK2, not all KRASG12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRASG12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRASG12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.

Keywords

Mice, Animals, Proto-Oncogene Proteins p21(ras), ras Proteins, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Mutation, Inflammation, Guanosine Triphosphate, KRASG12D, NRAS, IKK2, inflammation, oncogene activation, pancreatic cancer

Published Open-Access

yes

Recommended Citation

Ma, Jianjia; Gong, Fanghua; Kim, Eunice; et al., "Early Elevations of Ras Protein Level and Activity Are Critical for the Development of Pdac in the Context of Inflammation" (2024). Faculty, Staff and Student Publications. 4582.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4582