Our previous studies have shown that
benzyl isothiocyanate (BITC) suppresses pancreatic
tumor growth by inhibiting STAT-3; however, the exact mechanism of
tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic
tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1
pancreatic cancer cells in a dose dependant manner. Moreover, secretion of
VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both
VEGF and MMP-2 play a critical role in angiogenesis and
metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of
VEGFR-2 (Tyr-1175), and expression of HIF-α.
Rho-GTPases, which are regulated by
VEGF play a crucial role in
pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of
tumor suppressor RhoB. STAT-3 over-expression or
IL-6 treatment significantly induced HIF-1α and
VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1α and
VEGF expression. Finally, in vivo
tumor growth and
matrigel-plug assay show reduced
tumor growth and substantial reduction of
hemoglobin content in the
matrigel plugs and
tumors of mice treated orally with 12 µmol BITC, indicating reduced
tumor angiogenesis. Immunoblotting of BITC treated
tumors show reduced expression of STAT-3 phosphorylation (Tyr-705), HIF-α,
VEGFR-2,
VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic
tumor growth by inhibiting
tumor angiogenesis through STAT-3-dependant pathway.