Abstract 2707: Heat shock protein 90 functional inhibition regulates epithelial to mesenchymal transformation, invasion and migration via NF-kB and HIF-1α signaling in colorectal cancer

Purpose/Objectives: Epithelial to mesenchymal transformation (EMT), invasiveness and motility are essential steps in cancer metastasis. HIF-1α and NF-κB have a central role in cancer metastasis. These transcriptional factors (HIF-1α and NF-κB) required HSP90 for stability, folding and trafficking. Ganetespib is a potent functional inhibitor of HSP90 currently under evaluation in clinical trials. We tested the hypothesis that HSP90 functional inhibition by ganetespib can inhibit metastasis in colorectal cell lines. Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50 nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on different signal molecules involved in metastasis. Electrophoretic mobility shift assay (EMSA) was performed in CRC cells to evaluate the effects of ganetespib on NF-kB activity. Immunocytochemistry assay was also performed. Results: the treatment of colorectal cell lines with ganetespib can inhibit NF-κB and HIF-1α at transcriptional and translational level resulting in inhibition of EMT, invasion and motility. Our investigation also showed that ganetespib treatment significantly (p