Heat Shock Protein 90 Promotes Epithelial to Mesenchymal Transition, Invasion, and Migration in Colorectal Cancer

Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1 alpha and NF-kappa B. Since HSP90 activates HIF-1 alpha and NF-kappa B, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1 alpha and NF-kappa B resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1 alpha or NF-kappa B resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1 alpha and NF-kappa B leading to inhibition of EMT, motility, and invasiveness in colorectal cancer. (C) 2014 Wiley Periodicals, Inc.