Abstract 1508: SLPI enhances the expression of PLSCR1 in the HEY-A8 ovarian cancer cell line

Abstract

Abstract Secretory leukocyte protease inhibitor (SLPI) is a secreted protease inhibitor that governs inflammation and whose importance has been demonstrated in both pathologic and non-pathologic states. We have defined SLPI as an influential component of the tumor microenvironment promoting growth, survival, and tumor aggressiveness in ovarian cancer. Extracellular SLPI interacts with progranulin, an ovarian cancer growth factor and parental molecule of the pro-inflammatory granulins. Recently, intracellular SLPI has been shown to bind to the cytosolic domain of phospholipid scramblase 1 (PLSCR1) in CD4 T-cells. PLSCR1 is a ubiquitous transmembrane proinflammatory protein with oncogenic properties. PLSCR1 overexpression has been identified in malignant colorectal cancer and xenograft tumor models with increased metastatic and invasive potential. We hypothesized that SLPI remains cytosolic or reenters the cytosol from the tumor microenvironment where SLPI can influence its intracellular receptor, PLSCR1. Preliminary western blot data demonstrated PLSCR1 protein expression in both OVCAR8 and HEY-A8 human ovarian cancer cells with OVCAR8 expressing far less PLSCR1. OVCAR8 is also known, from previous studies, to express less SLPI than Hey-A8 cells. These data led us to investigate SLPI and PLSCR1 interactions using confocal microscopy where we stained HEY-A8 cells and found colocalization of SLPI and PLSCR1. Using HEYA8 with constitutively forced expression of SLPI and protease inhibitor null mutant Leu71PheSLPI, we examined the effect of SLPI on PLSCR1. The increased secretion of SLPI in these stably transfected cells is associated with increased PLSCR1 expression regardless of protease inhibitor activity; additional mutants are currently under examination. These data suggest a positive feedback mechanism between SLPI and its intracellular receptor, PLSCR1 in human ovarian cancer cells. Inhibition of SLPI, already credentialed as a molecular target in ovarian cancer, may be enhanced by interruption of its effects on PLSCR1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1508. doi:10.1158/1538-7445.AM2011-1508