Parthenolide suppresses hypoxia-inducible factor-1α signaling and hypoxia induced epithelial-mesenchymal transition in colorectal cancer

Activation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) is frequently observed in solid tumors and it has been associated with various pathophysiological processes, including epithelial-mesenchymal transition (EMT). Previously, we reported that parthenolide (PT), an inhibitor of nuclear factor-kappa B (NF-kappa B), is a promising anticancer agent because it promotes apoptosis of human colorectal cancer (CRC). Here, we investigated a new molecular mechanism by which PT acts on HIF-1a and hypoxia contributing to EMT by NF-kappa B inhibition. Cell viability, DNA binding activity, vascular cell tube formation and cell motility were studied after treatment of PT in hypoxic or normoxic condition. Moreover, effects of PT on hypoxia signaling and hypoxia- induced EMT signaling were investigated. We also examined the inhibitory effect of PT on CRC progression in xenografts. We demonstrated that PT markedly inhibits hypoxia dependent HIF-1 alpha activity and angiogenesis by preventing NF-kappa B activation. We also report that PT decreases the level of proteins associated with glucose metabolism, angiogenesis, development and survival that are regulated by HIF-1a. Furthermore, we verified that PT protects the morphological change from epithelial to mesenchymal state, inhibits matrix metalloproteinase (MMP) enzyme activity and decreases cell motility involved in the regulation of the hypoxia- induced EMT markers. In addition, PT inhibits growth in CRC xenograft models and regulates NF-kappa B, HIF-1 alpha a and EMT specific marker in tissue specimens. Our data demonstrated that PT can inhibit HIF-1 alpha signaling and hypoxia- induced EMT, suggesting a novel molecular mechanism for HIF-1 alpha mediated cancer progression and metastasis.