Targeting Lipolysis in Pancreatic Cancer Microenvironment Induces Lipid Peroxidation and Suppresses Cancer Cells Growth
Free Radical Biology and Medicine
Human pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates, at 11% suggesting that PDAC cells may be resistant to standard of care therapies. Previously, we have shown that stromal fibroblasts produce lipid metabolites that contribute to PDAC progression and therapy resistance. Here, we examined free fatty acid (FFA) levels in various cell types found in the PDAC microenvironment. Data showed fibroblasts and cancer associated fibroblasts have higher levels of FFA (4-8 fold) compared to stellate cells, suggesting fibroblasts can be a major source of metabolic supplements providing mitogenic signals within the PDAC microenvironment. We investigated if targeting FFA metabolism in the PDAC microenvironment can suppress PDAC progression. We used hypolipidemic agents (lipolysis inhibitors): Acipimox (Olbetam-Pfizer) and Atglistatin to down-regulate FFA levels in PDAC cells co-cultured with or without fibroblasts. Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) expressing PDAC cells and real-time live cell imaging was used to measure cell proliferation and cell cycle progression. Results showed 2-3 fold decrease in
he proliferation index in both PDAC alone and co-cultured with fibroblasts. The decrease in proliferation index was accompanied by an increase in G1 fraction in treated vs control cells. Next, we examined if the hypolipidemic agents induced growth inhibition were results of metabolic oxidative stress due to FFA deprivation in PDAC cells. Using lipid peroxides sensor BODIPY C11 to measure the ratio of oxidized vs neutral lipids in control and treated cells, data showed a 2-fold increase in the ratio of oxidized lipids vs neutral lipids in treated PDAC cells compared to controls. These results suggest targeting FFA metabolism in the PDAC microenvironment can suppress cancer cell progression through the activation of a metabolic G1 checkpoint. Repurposing hyperlipidemic agents for adjuvant therapy to the current standard of care may potentially enhance outcomes for PDAC patients.
Hebbert K, Wojtas A, Pearson K, Kennedy J, Sarsour E. Targeting Lipolysis in Pancreatic Cancer Microenvironment Induces Lipid Peroxidation and Suppresses Cancer Cells Growth. Free Radical Biology and Medicine. 2022; 192(S1). doi: 10.1016/j.freeradbiomed.2022.10.182.