title: Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma.
abstract: Hypoxia is a common feature of solid tumors, which controls multiple aspects of cancer progression. One important function of hypoxia and the hypoxia-inducible factors (HIF) is the maintenance of cancer stem-like cells (CSC), a population of tumor cells that possess stem cell-like properties and drives tumor growth. Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here, we show that glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found that these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacologic inactivation of HSP90 inhibited the increase in HIF levels and abolished the self-renewal and tumorigenic properties of CSCs induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors. Cancer Res; 76(19); 5845-56. ©2016 AACR.
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Filatova
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany. Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Seidel
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany.
authors.forename: Nuray
authors.initials: N
authors.lastname: Böğürcü
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gräf
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany.
authors.forename: Boyan K
authors.initials: BK
authors.lastname: Garvalov
authors.affiliation: Institute of Neuropathology, University of Giessen, Giessen, Germany. Till.Acker@patho.med.uni-giessen.de.
authors.forename: Till
authors.initials: T
authors.lastname: Acker
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D064828:Prolyl Hydroxylases / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064828:Prolyl Hydroxylases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human