Lung cancer is the second most prevalent form of cancer, the leading cause of cancer-related mortality, and disproportionately affects underserved minority populations. The five-year survival rate is a dismal 15 percent - emphasizing the need to develop novel biomarkers and therapeutic targets for early detection and selective treatment, respectively. The majority of lung cancers are associated with increased inflammation, as evidenced by elevated cyclooxygenase (COX) expression and synthesis of COX-derived prostaglandins, including prostaglandin E2 (PGE2). These bioactive lipids have emerged as central regulators of carcinogenesis in a variety of tissues, including the lung. In particular, modulation of PGE2 synthesis is strongly correlated with lung carcinogenesis: PGE2 is elevated in lung tumors. Increased levels of PGE2 promote lung carcinogenesis by increasing cell growth and invasion while PGE2 depletion inhibits lung carcinogenesis. Identification of pharmaceuticals that reduce prostaglandin synthesis is an active area of research. Pharmacological inhibition of the inducible COX-2 enzyme has been explored, however its use is associated with potentially lethal side effects. Our laboratory is examining the modulatory role of a novel cytochrome P450, CYP2S1, in lung carcinogenesis. We hypothesize that changes in CYP2S1 expression and enzymatic function, through genetic variants, regulates PGE2 synthesis in human lung cancer cells to modulate PGE2-associated cell growth and invasion. This hypothesis is supported by: i) CYP2S1 mediated metabolism of the PGE2 precursor prostaglandin G2 (PGG2) at near physiological levels - ultimately reducing PGE2 synthesis, and ii) our preliminary data, consistent with this role, showing: CYP2S1's expression is inversely related to intracellular PGE2 levels and that CYP2S1 depletion, and subsequent increased PGE2 levels, promotes cell migration in human bronchial epithelial cells (BEAS-2B). Furthermore, we have modeled a genetic polymorphism, associated with cancer and uniquely distributed among African American populations, near the opening of a putative substrate access channel - potentially implicating CYP2S1 polymorphisms to lung carcinogenesis in this population. We will address our hypothesis, and determine the impact of CYP2S1 expression (Aim1) and function (Aim2), on lung carcinogenesis using a combination of cell-based and biochemical approaches. This proposal is significant because it: i) establishes an important biological role for CYP2S1 in modulating prostaglandin synthesis and PGE2-associated phenotypes in lung cancer, ii) suggests a protective role for elevated expression of CYP2S1 in epithelial-derived cancer, and iii) develops sensitive biochemical and cell-based approaches for the future testing of CYP2S1-selective pharmaceuticals. These studies have the potential to alter current research, and potential future clinical, paradigms.
Lung cancer is the leading cause of cancer-related mortality, disproportionately affecting underserved minority populations. This project will determine the underlying mechanism associating CYP2S1 with cancer, particularly of the lung, and generate the foundation for evaluating CYP2S1 as a novel new cancer biomarker and/or drug target.
|Madanayake, Thushara W; Lindquist, Ingrid E; Devitt, Nicholas P et al. (2013) A transcriptomic approach to elucidate the physiological significance of human cytochrome P450 2S1 in bronchial epithelial cells. BMC Genomics 14:833|
|Madanayake, T W; Fidler, T P; Fresquez, T M et al. (2012) Cytochrome P450 2S1 depletion enhances cell proliferation and migration in bronchial epithelial cells, in part, through modulation of prostaglandin E(2) synthesis. Drug Metab Dispos 40:2119-25|