Tumor metastasis is the main cause of lethality of
prostate cancer, because conventional
therapies like surgery and
hormone treatment rarely work at this stage.
Tumor cell migration, invasion and adhesion are necessary processes for
metastasis. By providing nutrition and an escape route from the primary site, angiogenesis is also required for
tumor metastasis.
Phosphatidylinositol 3-kinases (PI3Ks) are well known to play important roles in
tumorigenesis as well as
metastasis.
ZSTK474 is a specific PI3K inhibitor developed for solid
tumor therapy. In the present report, antimetastatic activities of
ZSTK474 were investigated in vitro by determining the effects on the main metastatic processes.
ZSTK474 exhibited inhibitory effects on migration, invasion and adhesive ability of
prostate cancer PC3 cells. Furthermore,
ZSTK474 inhibited phosphorylation of Akt substrate-Girdin, and the secretion of
matrix metalloproteinase (
MMP), both of which were reported to be closely involved in migration and invasion. On the other hand,
ZSTK474 inhibited the expression of HIF-1α and the secretion of
vascular endothelial growth factor (
VEGF), suggesting its potential antiangiogenic activity on PC3 cells. Moreover, we demonstrated the antiangiogenesis by determining the effect of ZSTK474-reduced
VEGF on tube formation of human umbilical vein endothelial cells (HUVECs). In conclusion,
ZSTK474 was demonstrated to have potential in vitro antimetastatic effects on PC3 cells via dual mechanisms: inhibition of metastatic processes including cell migration, invasion and adhesion, and antiangiogenesis via blockade of
VEGF secretion.