Butyrate Impairs Intestinal Tumor Cell-induced Angiogenesis by Inhibiting HIF-1alpha Nuclear Translocation

Butyrate is known to stimulate proliferation of normal crypt cells, whereas it inhibits growth and induces apoptosis in colon cancer cells. We examined the effects of butyrate on colon cancer (Caco-2) cell-induced angiogenesis. HUVEC proliferation was significantly inhibited when incubated with medium conditioned by butyrate-treated Caco-2 cells. Simultaneously, levels of the proangiogenic vascular endothelial growth factor (VEGF) were reduced. HIF-1alpha protein, a transcription factor known to be a key regulator in hypoxia-induced angiogenesis, was upregulated by butyrate. This is in contrast to its importance as a VEGF regulating component. However Western blot of nuclear extracts revealed a downregulation of HIF-1alpha protein. HIF-1alpha DNA-binding activity was also decreased by butyrate. Our findings indicate that HIF-1alpha nuclear sequestration is repressed by butyrate, through inhibition of nuclear translocation. We postulate that diminished HIF-1alpha nuclear presence and activity in butyrate-treated Caco-2 cells could be responsible for decreased VEGF expression and antiangiogenic effects.