Fatty Acid Binding Protein 4 Alters Obesity Associated Cancer Metabolism via Lipid Desaturation and Redox Signaling

University of Minnesota M.S. thesis. May 2019. Major: Surgery. Advisors: Masato Yamamoto, Sayeed Ikramuddin. 1 computer file (PDF); viii, 29 pages.Background: An association of obesity with cancer incidence and worsened clinical outcomes has been established. Circulating and local levels of fatty acid binding protein 4 (FABP4), a lipid chaperone and adipokine, have been correlated with degree of obesity and metabolic dysfunction, and more recently with breast and pancreas cancer prognosis. FABP4 transcriptional regulation has been linked to cellular redox status, with nuclear factor (erythroid-derived 2)-like 2 (Nrf2) being an upstream regulator of this balance. We hypothesized FABP4 modifies fatty acid saturation indices in cancer, driving an altered redox status, and ultimately inducing tumor proliferation. Methods: Panc1 pancreatic adenocarcinoma and MCF7 breast cancer cells were treated with recombinant FABP4, R126Q (FABP4 point mutant), and HTS01037 (FABP4 inhibitor.) Cell growth and proliferation was assessed. Targeted lipidomic analysis was performed in the same conditions. Whole cell reactive oxygen species (ROS) was quantified via Amplex Red assay. Nrf2 activity was quantified via antioxidant response element luciferase assay, and cell proliferation with chemical inhibitor (brusatol) was assessed. Untargeted gene expression profiles after FABP4 or HTS treatment were studied via RNA sequencing. C57BL/6J FABP4 knockout (AKO) and littermate wild type (WT) mice were injected with Pan02 and E0771 cells, murine pancreas and breast cancer cell lines. Tumor volume and progression was evaluated. Results: Panc1 and MCF7 cells treated with recombinant FABP4 demonstrated increased proliferation relative to control and point mutant protein treatment. This increase was abolished with HTS treatment. Unsaturated/saturated fatty acid ratio was decreased with FABP4 treatment and increased with HTS treatment. ROS levels were decreased and Nrf2 activity was concurrently increased with exposure to exogenous FABP4. Nrf2 gene expression profile was upregulated with FABP4 treatment, independent of ER stress. Tumor progression was significantly decreased in AKO mice. Conclusions: FABP4 induces a shift in the fatty acid saturation index of tumor cells, activating Nrf2 expression and decreasing intracellular ROS, independent of ER stress, allowing for aggressive tumor proliferation