The actin filament associated protein (AFAP-110) is overexpressed and contributes to prostate carcinoma development by regulating PKC α-mediated fibronectin expression

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 2459 The actin filament-associated protein, AFAP-110, first identified as a classic substrate of the non-receptor tyrosine kinase, Src, was subsequently implicated in protein kinase Cα (PKCα) signaling. Parallel with the important roles of several other Src substrates in human tumor development and progression, we demonstrate that AFAP-110 expression contributes to human prostate cancer growth. Using prostate tissue arrays, we found that AFAP-110 was absent or expressed at very low levels in normal prostatic epithelium and benign prostatic hyperplasia, but was significantly increased in prostate carcinomas. Additionally, the expression of AFAP-110 positively correlated with Gleason grades, indicating a potential role in prostate cancer progression. Down-regulation of AFAP-110 in PC3 prostate cancer cells resulted in decreased cell proliferation and anchorage-independent growth in vitro, as well as reduced tumor incidence and growth in orthotopic nude mouse models. Furthermore, down-modulation of AFAP-110 significantly decreased cell-matrix adhesion and migration, correlating with reduced focal adhesions. To further understand the underlying molecular mechanisms by which AFAP regulates prostate cancer growth, we utilized an extracellular matrix (ECM) and adhesion molecule mRNA microarray and identified a significant decrease in fibronectin expression in AFAP-110 down-regulated clones, accompanied by reduced protein level of major fibronectin receptor, integrin α5β1. In agreement with AFAP-110 affecting PKCα signaling, down-regulation of AFAP-110 decreased PKCα-mediated fibronectin expression. These data suggest that AFAP-110 regulates critical signaling pathways governing PKCα-mediated ECM protein expression in regulating prostate cancer cell adhesiveness and motility. Thus, AFAP-110 may be a novel prognostic marker for prostate cancer that functions, in part, by regulating cell-ECM interaction.