Abstract
Targeting arachidonic acid lipoxygenase-12 (ALOX12) in the pancreatic ductal adenocarcinoma tumor microenvironment to enhance therapy outcomes
Free radical biology & medicine, Vol.240(Suppl 1), p.S41
11/2025
DOI: 10.1016/j.freeradbiomed.2025.10.119
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of around 11%, largely due to its resistance to therapy. Research indicates that the tumor microenvironment, particularly fibroblasts expressing arachidonic acid lipoxygenase-12 (ALOX12), plays a critical role in this resistance. ALOX12 overexpression leads to high levels of 12(S)-hydroxyeicosanoic acid (12(S)-HETE), which promotes cancer cell proliferation. This study hypothesized that inhibiting ALOX12, in combination with chemotherapy, could suppress PDAC proliferation and enhance therapy effectiveness. Using the novel ALOX12 inhibitor code named Slug001, the production of 12(S)-HETE was significantly reduced in normal human fibroblasts (NHFs) from individuals over 50 years old. ELISA assays confirmed up to 90% inhibition of 12(S)-HETE with Slug001 treatment. A co-culture system of NHFs and Mia PaCa-2 PDAC cells, engineered with the fluorescent ubiquitination cell cycle indicator (FUCCI) system, was used to observe real-time effects on cancer cell growth and cell cycle progression. The combination of Slug001 and chemotherapy resulted in the lowest growth index of PDAC cells, up to 60% inhibition when comparing to chemotherapy alone, suggesting Slug001 reduce resistance to therapy. Further, phosphorylation assays showed decreased activity in several pro-proliferative MAP kinase pathways including ERK1/2, RSK1 and PDK1 upon Slug001 treatment, indicating an inhibitory effect on cancer cell proliferation. These findings support the hypothesis that targeting ALOX12 within the PDAC tumor microenvironment can significantly enhance the efficacy of chemotherapy, offering a promising adjuvant treatment strategy.
Details
- Title: Subtitle
- Targeting arachidonic acid lipoxygenase-12 (ALOX12) in the pancreatic ductal adenocarcinoma tumor microenvironment to enhance therapy outcomes
- Creators
- Sarila EkinAlexis PaynterAdora KlinestiverPrabhat C. GoswamiTed HolmanEhab H. Sarsour
- Resource Type
- Abstract
- Publication Details
- Free radical biology & medicine, Vol.240(Suppl 1), p.S41
- DOI
- 10.1016/j.freeradbiomed.2025.10.119
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- ELSEVIER SCIENCE INC
- Language
- English
- Date published
- 11/2025
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9985024258402771
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