title: The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1α in cancer cells, induces cell death, and reduces tumor xenograft growth.
abstract: The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs). HIF-1α is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1α under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs). Here, we identified a high level of normoxic HIF-1α protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity. We tested the ability of several cell-permeable 2-oxoglutarate analogs to regulate the abundance of HIF-1α protein. We identified 3-oxoglutarate as a potent regulator of HIF-1α in normoxic conditions. In contrast to 2-oxoglutarate, 3-oxoglutarate decreased the abundance of HIF-1α protein in several cancer cell lines in normoxia and diminished HIF-1α levels independent of EGLN enzymatic activity. Furthermore, we observed that 3-oxoglutarate was detrimental to cancer cell survival. We show that esterified 3-oxoglutarate, in combination with the cancer chemotherapeutic drug vincristine, induces apoptosis and inhibits tumor growth in vitro and in vivo. Our data imply that a novel treatment strategy targeting HIF-1α in combination with the use of existing cytotoxic agents could serve as potent, future antitumor chemotherapies.
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Fell
authors.affiliation: Department of Chemistry and Integrative Genomics, Princeton University, Princeton, NJ.
authors.forename: Wenyun
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Integrative Genomics, Princeton University, Princeton, NJ.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Stockholm, Sweden; Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schlisio
keywords: 3-oxoglutarate; EGLN; HIF; cancer; hypoxia; prolyl hydroxylase