title: HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization.
abstract: The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor-1α (HIF1α) and activation of NF-κB in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1α and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-κB/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth.
authors.affiliation: Center for Internal Medicine I, University of Ulm, Ulm, Germany. ninel.azoitei@uni-ulm.de.
authors.forename: Ninel
authors.initials: N
authors.lastname: Azoitei
authors.affiliation: Center for Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Diepold
authors.affiliation: Institute for Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brunner
authors.affiliation: Center for Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Arefeh
authors.initials: A
authors.lastname: Rouhi
authors.affiliation: Department of Urology, University of Ulm, Ulm, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.affiliation: Center for Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Becher
authors.affiliation: Institute for Neuroinformatic, Ulm University, Ulm, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kestler
authors.affiliation: Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: van Lint
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Institute, New York, New York.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Institute, New York, New York.
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: Center for Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Center for Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; C089212:protein kinase D; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex