Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.
4 affiliations
- 1University of Arizona Cancer Center, Tucson, AZ, USA.
- 2Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ, USA.
- 3University of Arizona Cancer Center, Tucson, AZ, USA. [email protected].
- 4Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ, USA. [email protected].
Abstract
Oncogenic mutations in the K-RAS small GTPase occur in more than 90% of human PDACs and cause dysregulation of multiple metabolic pathways, including polyamine metabolism. The goal of this study was to determine whether blocking polyamine synthesis with the irreversible inhibitor α-difluoromethylornithine (DFMO) provides a valid approach to targeting metabolic dependency in mutant K-RAS pancreatic tumors, compared with direct suppression of the oncogenic K-RAS protein. The anti-tumor activity of DFMO was evaluated in vitro and in vivo in the MIA PaCa-2 pancreatic cell line (K-RASG12C) and its isogenic clonally selected line M-27, which does not express a functional GTP-bound RAS protein. MIA PaCa-2 and M-27 cells had comparable intracellular polyamine levels, and DFMO treatment effectively suppressed total polyamine levels in both cell lines (p < 0.01). DFMO reduced the protein levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and RAS-like small GTPase A (RalA) but induced the phosphoinositide 3-phosphate kinase (PI3K) signaling pathway. Additionally, the intracellular levels of K-RAS and hypusinated eukaryotic initiation factor 5 A (eIF5AHyp) proteins were suppressed in DFMO-treated MIA PaCa-2 cells. DFMO therapy regimen (500 mg/kg/day by oral gavage) significantly improved survival rates of SCID mice with orthotopically implanted MIA PaCa-2 cell line (MIA PaCa-2 control vs. MIA PaCa-2 DFMO, p = 0.0184), with median survival time comparable to animals implanted with M-27 cell line (MIA PaCa-2 control vs. M-27 control, p = 0.0204). DFMO treatment did not significantly improve survival of mice bearing M-27 tumors (M-27 control vs. M-27 DFMO, p = 0.6055). These data indicate that DFMO treatment suppresses pancreatic tumorigenesis driven by the mutant K-RAS oncogene similarly to the targeted elimination of the active GTP-bound RAS protein.
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BibTeX
@article{chen2026difluoromethylornithine,
title = {{Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.}},
author = {Hwudaurw Chen and David E Stringer and Haiyan Cui and Eugene W Gerner and Natalia A Ignatenko},
journal = {Amino acids},
year = {2026},
month = sep,
doi = {10.1007/s00726-026-03559-5},
url = {https://europepmc.org/article/MED/42892656},
note = {CC BY},
}
RIS
TY - JOUR
TI - Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.
AU - Hwudaurw Chen
AU - David E Stringer
AU - Haiyan Cui
AU - Eugene W Gerner
AU - Natalia A Ignatenko
PY - 2026
DA - 2026/09/16
JO - Amino acids
DO - 10.1007/s00726-026-03559-5
UR - https://europepmc.org/article/MED/42892656
AB - Oncogenic mutations in the K-RAS small GTPase occur in more than 90% of human PDACs and cause dysregulation of multiple metabolic pathways, including polyamine metabolism. The goal of this study was to determine whether blocking polyamine synthesis with the irreversible inhibitor α-difluoromethylornithine (DFMO) provides a valid approach to targeting metabolic dependency in mutant K-RAS pancreatic tumors, compared with direct suppression of the oncogenic K-RAS protein. The anti-tumor activity of DFMO was evaluated in vitro and in vivo in the MIA PaCa-2 pancreatic cell line (K-RASG12C) and its isogenic clonally selected line M-27, which does not express a functional GTP-bound RAS protein. MIA PaCa-2 and M-27 cells had comparable intracellular polyamine levels, and DFMO treatment effectively suppressed total polyamine levels in both cell lines (p < 0.01). DFMO reduced the protein levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and RAS-like small GTPase A (RalA) but induced the phosphoinositide 3-phosphate kinase (PI3K) signaling pathway. Additionally, the intracellular levels of K-RAS and hypusinated eukaryotic initiation factor 5 A (eIF5AHyp) proteins were suppressed in DFMO-treated MIA PaCa-2 cells. DFMO therapy regimen (500 mg/kg/day by oral gavage) significantly improved survival rates of SCID mice with orthotopically implanted MIA PaCa-2 cell line (MIA PaCa-2 control vs. MIA PaCa-2 DFMO, p = 0.0184), with median survival time comparable to animals implanted with M-27 cell line (MIA PaCa-2 control vs. M-27 control, p = 0.0204). DFMO treatment did not significantly improve survival of mice bearing M-27 tumors (M-27 control vs. M-27 DFMO, p = 0.6055). These data indicate that DFMO treatment suppresses pancreatic tumorigenesis driven by the mutant K-RAS oncogene similarly to the targeted elimination of the active GTP-bound RAS protein.
SN - 0939-4451
SN - 1438-2199
ER -