Fatty Acid Metabolizing Cytochrome P450 4F11 as a Novel Drug Target for Lung Cancer Treatment

Abstract ID 94647 Poster Board 230 Lung cancer is the leading cause of cancer deaths worldwide. Lung cancer patients often develop drug resistance during therapy, hence, identifying new therapeutic targets is important for alternative treatment approaches. The potent lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) regulates the blood pressure in humans. However, 20-HETE also promotes cell proliferation and migration in cancer. It is generated by the cytochrome P450 (P450, CYP) family 4A/F through a selective ω-hydroxylation of arachidonic acid. The unselective inhibition of 20-HETE-producing CYP4 enzymes attenuates the lung cancer tumor growth in xenograft mouse models, yet the clinical exploitation of CYP4 enzymes as drug targets has not been realized due to a lack of functional and structural studies. The isoform CYP4F11 is the only w-hydroxylase that is significantly overexpressed in lung tumor tissue. However, the exact role of CYP4F11 in lung cancer has not been established yet. We hypothesize that CYP4F11-mediated 20-HETE production promotes lung cancer cell proliferation and migration and that CYP4F11 is a novel drug target for lung cancer therapy. To investigate the role of CYP4F11 in lung cancer, the impact of CYP4F11 on cell proliferation and migration was first investigated by knocking down and overexpressing CYP4F11 in three lung cancer cell lines with different CYP4F11 expression levels. We found that the knockdown of CYP4F11 significantly inhibits lung cancer cell proliferation and migration while a CYP4F11 overexpression promotes both when compared to control cells. We confirmed that the 20-HETE levels were significantly decreased in knockdown cells compared to control cells. The addition of exogenous 20-HETE rescued the cell proliferation back to control cell levels. To further evaluate the role of CYP4F11 as a therapeutic target, we first measured the catalytic efficiency of recombinant CYP4F11 and found that CYP4F11 only poorly metabolizes arachidonic acid. We then evaluated the inhibitory effect of the CYP4 pan inhibitor HET0016 on CYP4F11. HET0016 binds tightly to CYP4F11 and inhibits 20-HETE production with high inhibitory efficiency. Unfortunately, the efficacy of HET0016 is low when applied to lung cancer cell lines and exhibits serious off-target effects. However, HET0016 might provide a scaffold for future structure-based drug design. Ongoing studies are focused on other CYP4F11 substrates that have an implication on lung cancer growth such as the endocannabinoid anandamide and the eicosanoid 15-HETE which both are metabolized by CYP4F11. Thus, the high expression of CYP4F11 in lung cancer might not only affect 20-HETE production but also other lipid mediators with an impact on cell proliferation and migration. Our studies show that CYP4F11 is a potential new drug target for lung cancer therapeutics. Future studies aim to elucidate metabolic pathways affected by CYP4F11 expression and the metabolism of additional lipid mediators with an implication on lung cancer proliferation and migration. This research was funded by a New Investigator Award of the American Association from Colleges of Pharmacy (AACP) and start-up funds from the University of Pittsburgh School of Pharmacy.