title: Heat shock protein 90 promotes epithelial to mesenchymal transition, invasion, and migration in colorectal cancer.
abstract: Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM 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-1α or NF-κB 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-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer.
authors.affiliation: Department of Hematology Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.|School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Tua-Elisabeth
authors.initials: TE
authors.lastname: Long
authors.affiliation: School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Wungki
authors.initials: W
authors.lastname: Park
authors.affiliation: School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Landry
authors.affiliation: Department of Hematology Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.|School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: LaTonia
authors.initials: L
authors.lastname: Taliaferro-Smith
authors.affiliation: Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Roberto
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Department of Hematology Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.|School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D003094:Collagen / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004338:Drug Combinations; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007797:Laminin / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011509:Proteoglycans / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D014746:Vimentin / Q000235:genetics
chemical_list: D015820:Cadherins; D004338:Drug Combinations; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D014746:Vimentin; C059485:matrigel; D003094:Collagen
keywords: EMT; HSP90; colorectal cancer; ganetespib; metastasis