Investigators

Summary

Research in my laboratory is focused on cytochrome P450 enzymes (P450), their role in human health and disease, and their potential as drug targets. While most studies focus on steroidogenic P450 enzymes as drug targets for prostate and breast cancer treatment, my goal is to evaluate the potential of targeting fatty acid metabolizing P450 enzymes for cancer therapy. I am particularly interested in the CYP4F enzyme family of fatty acid -hydroxylases which, according to our findings, are upregulated in several cancer type. CYP4F enzymes are involved in the metabolism of arachidonic acid to the potent lipid mediator 20-hydroxyeicosatetraenois acid (20-HETE). While 20-HETE regulates the blood pressure in healthy individuals, it also promotes cell proliferation and migration and tumor angiogenesis in cancer. An unselective inhibition of 20-HETE producing CYP4 enzymes leads to a significant decrease of lung tumor size in mouse models. However, the clinical exploitation of these enzymes has not been realized yet due to high protein sequence similarities, the absence of isoform specific inhibitors, and a substantial lack of structural and functional information. Our long term goal is to establish CYP4F enzymes as novel potential drug targets for cancer therapeutics. Recent efforts in my lab were focused on the isoform CYP4F11 in lung cancer. My team has shown for the first time that a transient CYP4F11 knockdown in lung cancer cell lines leads to decreased cell proliferation and migration which is associated with decreased 20-HETE production. We also generated recombinant human CYP4F11 protein to conduct in-depth biochemical studies to probe enzyme function and to solve structures of CYP4F11 using X-ray protein crystallography. We aim to examine other CYP4F isoforms in various cancer types, unravel their cellular function in addition to 20-HETE production, and solve protein structures for the directed design of selective drugs.