Date of Award
Master of Science
Jennifer A. Doll
Jeri A. Lyons, Dean T. Nardelli
Prostate cancer (PCa) is the most common type of cancer diagnosed in American men. Cancer progression is associated with increased angiogenesis, and thrombospondin-1 (TSP–1) and pigment epithelium derived factor (PEDF), both potent anti-angiogenic molecules, are downregulated in PCa cells. TSP-1 exerts its activity through binding to several cell surface receptors such as CD36. Both TSP-1 and PEDF are multi-functional proteins and have been linked to lipid metabolism in other cell types. Moreover, TSP-1 - PEDF regulatory loops have been identified in some cell types. PEDF has been shown to inhibit PCa growth through its effects on angiogenesis and directly on the PCa cells; however, how PEDF expression levels are regulated in prostate cells is currently unknown. Here, we hypothesized that TSP-1 may regulate PEDF expression and lipid metabolism in PCa cells.
I collected and examined PEDF levels in both cell lysate and serum-free conditioned media samples from TSP-1 and anti-CD36 antibody treated prostate cells and examined PEDF levels. Both TSP-1 and anti-CD36 treatment increased PEDF expression in normal prostate epithelial cells, RWPE-1, and in PCa cells, PC-3 and LNCaP. The expression of candidate TSP-1 - CD36 signaling mediators, fyn, p38 MAPK and JNK, were also examined in treated samples. I found that TSP-1 treatment elevated expression of fyn, p38 and JNK in PC-3 and DU145 cells. In contrast, blocking the CD36 receptor diminished the expression of each signaling mediator.
My results are the first to show that a regulatory loop exists between TSP-1 and PEDF in prostate cells. The observation that treatment with anti-CD36 antibody also increased PEDF suggests that TSP-1 regulation of PEDF may be mediated through the CD36 receptor. These observations suggest that one mechanism of PEDF down-regulation in PCa cells may be due to loss of TSP-1 expression. Moreover, this pathway could be exploited for novel therapeutic interventions.
Chawla, Ayesha, "Regulation of Anti-Angiogenic Pedf Through a TSP-1 - CD36 Pathway in Prostate Cancer" (2013). Theses and Dissertations. 672.