Spliceostatin A (SSA) is a methylated derivative of an antitumor
natural product FR901464, which specifically binds and inhibits the SF3b spliceosome sub-complex. To investigate the selective antitumor activity of SSA, we focused on the regulation of
vascular endothelial growth factor (
VEGF)
mRNA, since
VEGF is a key regulatory component in
tumor angiogenesis and known for the intricate regulation of
mRNA processing, such as alternative splicing. We found that in HeLa cells SSA reduced the amount of both
mRNA and
protein of
VEGF.
Spliceostatin A not only inhibited the splicing reaction of
VEGF pre-mRNA but also reduced the total amount of
VEGF's transcripts, while SSA affected GAPDH
mRNA to a lesser extent. Given a significant reduction in
VEGF gene expression, SSA was expected to possess anti-angiogenic activity in vivo. Indeed, SSA inhibited
cancer cell-derived angiogenesis in vivo in a chicken chorioallantoic membrane (CAM) assay. The inhibition of angiogenesis with SSA was abolished by addition of exogenous
VEGF. We also performed global gene expression analyses of HeLa cells and found that the expression levels of 38% of total genes including
VEGF decreased to <50% of the basal levels following 16 h of SSA treatment. These results suggest that the global interference of gene expression including
VEGF in
tumor cells is at least one of the mechanisms by which SSA (or
FR901464) exhibits its strong antitumor activity.