Figure 8. A schematic overview of the potential mechanism involved in K5-mediated inhibition of HIF-1α in tumor cells.

K5 up-regulates VHL and consequently promotes ubiquitin-proteasome medicated protein degradation of HIF-1α. Moreover, K5 decreased HIF-1α protein stabilization, reduced nuclear HIF-1α accumulation and then inhibited transcriptional activation. Consequently, K5 down-regulated the gene expression of CXCR4 and VEGF, which were the downstream genes of HIF-1α pathway. VEGF and CXCR4 play key roles in angiogenesis and chemotaxis migration which both are requisites to metastasis promotion. This may be responsible for the dual inhibitory effects of K5 on tumor metastasis.