Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. Identification of significant tumor biomarkers and key pathogenic pathways is of paramount importance for ovarian cancer prognosis and treatment strategies. The etiopathologic pathways leading to the development of ovarian tumors involve mechanisms that are due to changes in activity rather than expression level of the target genes. We have initiated an activity-based proteomic profiling (ABPP) study to determine global activity status of serine hydrolase superfamily and found that in serous ovarian tumors there are elevated activities of several enzymes involved in an ether lipid metabolic signaling pathway, which results in the production of lysophosphatidic acids for tumor growth and progression. One such aberrantly active enzyme is platelet-activating factor acetylhydrolase I (PAF-AH I), which hydrolyzes platelet-activating factor (PAF). Treatments of ovarian cancer cells with PAF analogues that are non-hydrolysable by this enzyme showed significantly enhanced cancer cell death. We hypothesize that this enzyme plays a significant role in ovarian pathogenesis and targeting the PAF-AH I pathway may constitute an effective preventive and intervention strategy for ovarian cancer.
The specific aims of this proposal are: 1. To delineate the role of PAF-AH I enzyme in ovarian pathogenesis by ectopic expression in normal human ovarian surface epithelial (HOSE) cells and inhibition of the enzyme in ovarian cancer cell lines using short hairpin RNA (shRNA), and measure any changes in cell growth invasiveness, lipid signaling and metabolite profile;2. To evaluate the effects of selected PAF analogues on cancer cell viability, enzyme activity, lipid signaling and metabolites;and 3. To investigate if the expression, activity, and metabolite signatures of PAF-AH I pathway identified in Specific Aims One and Two have any significant correlations with clinicopathologic characteristics including survival of ovarian tumors. This innovative proposal integrates the studies of both the enzymatic proteome and its primary biochemical output (the metabolome). It is expected that identification and characterization of activity and metabolite signatures of the deregulated PAF-AH I pathway will have significant translational impact on diagnosis, surveillance, clinical management and overall outcome of ovarian cancer patients.
This project is focused on the studies of enzymatic activity and metabolomic signatures of an enzyme in a novel ether lipid metabolic and signaling pathway that is deregulated in ovarian cancer. Ether lipid analogues that are not hydrolysable by this enzyme have shown significant efficacies in killing cancer cells. Hence, our proposed study will have significant impacts on the prevention, clinical management, and treatment strategies of ovarian cancer patients.
| Benjamin, Daniel I; Louie, Sharon M; Mulvihill, Melinda M et al. (2014) Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. ACS Chem Biol 9:1340-50 |
