title: Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer.
abstract: Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.
authors.affiliation: Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Cavanaugh
authors.affiliation: Penn State University, Department of Plant Biology, State College, PA, USA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Juengst
authors.affiliation: Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sheridan
authors.affiliation: Department of Urology, Geisinger Health System, Danville, PA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Danella
authors.affiliation: Weis Center for Research, Geisinger Health System, Danville, PA, USA.|Department of Urology, Geisinger Health System, Danville, PA, USA.
authors.forename: Heinric
authors.initials: H
authors.lastname: Williams
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009132:Muscles / Q000473:pathology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011684:Purine Nucleosides / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D011684:Purine Nucleosides; D016160:Retinoblastoma Protein; C533237:STA 9090; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C550733:VER 155008; D019869:Phosphatidylinositol 3-Kinases
keywords: heat shock protein 70; heat shock protein 90; muscle invasive bladder cancer