(475) Targeting Cytochrome P450 Mediated Fatty Acid Metabolism in Lung Cancer

Objective : Lung cancer is the leading cause of cancer-related deaths. The lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) regulates the blood pressure in healthy individuals. However, in cancer 20-HETE promotes cell proliferation, invasion, and migration. 20-HETE is generated by members of the cytochrome P450 (CYP) family 4A/F. The isoform CYP4F11 is significantly overexpressed in patients with lung squamous carcinoma. However, the exact role of CYP4F11 in oncogenesis and its suitability as a drug target have not been established yet. We hypothesize that CYP4F11 is pivotal in lung cancer and a potent drug target for cancer treatment.

Methods: First, we performed a transient knockdown of CYP4F11 in lung cancer cell lines to assess the impact of CYP4F11 on cell proliferation and migration. Second, we conducted a preliminary screening for compounds inhibiting CYP4F11 using recombinant human CYP4F11.

Results: The cell viability and migration of CYP4F11 knockdown cells was significantly decreased compared to control cells indicating a pivotal role of CYP4F11 in lung cancer. Moreover, the production of 20-HETE was attenuated in CYP4F11 knockdown cells, and the addition of exogenous 20-HETE to knock down cells could rescue cell proliferation. We then evaluate the unselective CYP4A/F inhibitor HET0016 as a model drug for future drug design. In spectroscopic ligand binding studies, HET0016 shows high affinity to recombinant CYP4F11. Moreover, HET0016 attenuates cell proliferation in a dose dependent manner.

Conclusions: Our results show the potential of targeting CYP4F11 for lung cancer therapy. We aim to further establish the role of CYP4F11 in lung cancer and promote its use as drug target.