Dual Inhibition of PFKFB3 and ODC1 Exhibits Enhanced Antiproliferative Effect on Pancreatic Cancer Cells.
X. Multidisciplinary Cancer Research Congress , Eskişehir, Türkiye, 8 - 11 Mayıs 2025, ss.132, (Özet Bildiri)
- Yayın Türü: Bildiri / Özet Bildiri
- Basıldığı Şehir: Eskişehir
- Basıldığı Ülke: Türkiye
- Sayfa Sayıları: ss.132
- Bursa Uludağ Üniversitesi Adresli: Evet
Özet
Introduction: Pancreatic adenocarcinoma is one of the deadliest cancers, and incidence is on the rise. Activating mutations in the KRAS gene confers an aggressive metabolic phenotype in pancreatic adenocarcinoma, which may present therapeutic vulnerabilities. Hyperactive KRAS stimulates glycolysis that is associated with malignant properties, including chemoresistance, suggesting that targeting glycolysis may be a viable therapeutic strategy. Targeting glycolysis, particularly through the glycolytic regulator PFKFB3, offers a promising therapeutic strategy. The glycolytic regulator 6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) has been shown to be an attractive target to curb aberrant glycolytic activity in tumor cells. In this study, we set out to study the effect of dual targeting of PFKFB3 and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine synthesis pathway. Material and Methods: In this study, we explored the dual targeting of PFKFB3 and ornithine decarboxylase 1 (ODC1), the key enzyme in the polyamine synthesis pathway, in pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2. We utilized specific siRNA molecules to silence PFKFB3 and ODC1 expressions and employed clinical-grade inhibitors KAN0438757 and DFMO to block their enzymatic activities. Forty-eight hours after treatment, cell viability was assessed using sulforhodamine B and crystal violet assays. Clonogenic assays were also performed to evaluate colony formation after combined treatment. Results and Discussions: Dual silencing of PFKFB3 and ODC1 significantly suppressed cell proliferation compared to individual targeting. Additionally, subtoxic doses of KAN0438757 enhanced the sensitivity of pancreatic adenocarcinoma cells to DFMO treatment, further reducing clonogenic potential. These findings indicate that PFKFB3 and ODC1 may cooperate to sustain the proliferative and clonogenic abilities of pancreatic adenocarcinoma cells. Conclusion: Dual inhibition of glycolysis and polyamine synthesis via PFKFB3 and ODC1 targeting represents a potential therapeutic strategy to manage pancreatic adenocarcinoma more effectively.