Abstract
Activation of Rac by guanine-nucleotide exchange factors (GEFs) at the leading edge of the cell plays an important role in directional cell migration, a critical step of tumor metastasis cascades. We investigated the role of P-Rex1, a novel specific GEF for Rac, in human prostate cancer metastasis. P-Rex1 expression (mRNA and/or protein) was almost undetectable in normal prostate epithelial cells (PrEC) and two nonmetastatic prostate cancer cell lines (LNCaP and CWR22Rv1), but was clearly detectable in highly metastatic prostate cancer cell lines (PC3-LN4 and PC-3). Studies of human prostate tumor specimens revealed a 1.6-fold increase in P-Rex1 protein expression in localized cancer cells and a 3.7-fold increase in lymph node prostate metastasis when compared to noncancerous prostate tissues. Migration abilities of various prostate cancer cell lines determined by transwell chamber assays were directly correlated with their P-Rex1 expression levels. Silencing endogenous P-Rex1 expression significantly reduced cell migration ability in metastatic PC-3 cells. Stable expression of wild-type P-Rex1 but not its "GEF-dead" mutant increased CWR22Rv1 cell migration and invasion by 3-fold. Further study indicated that P-Rex1 promotes prostate cancer cell migration and invasion via Rac activation. Finally, in vivo studies revealed that expression of wild-type P-Rex1 but not Its "GEF-dead" mutant significantly promoted spontaneous metastasis of CWR22Rv1 cancer cells to mouse lymph nodes without effects on primary tumor growth. Altogether, our results identify P-Rex1 as an important regulator of prostate cancer metastatic progression and suggest that it may be targeted for prevention and treatment of prostate cancer metastasis.