title: Short-term treatment with glucosamine hydrochloride specifically downregulates hypoxia-inducible factor-1α at the protein level in YD-8 human tongue cancer cells.
abstract: Hypoxia-inducible factor-1 (HIF-1) is a tumor angiogenic transcription factor composed of an α and β subunit. We investigated the effect of glucosamine hydrochloride (GS-HCl) on the expression of HIF-1α and HIF-1β in serum‑treated YD-8 human tongue cancer cells. While long-term (24 h) treatment with GS-HCl strongly repressed the expression of HIF-1α and HIF-1β at both the protein and mRNA levels, short-term (4 h) GS-HCl treatment inhibited HIF-1α at the protein level. Short-term GS-HCl treatment also decreased phosphorylation of p70S6K and S6, translation-related proteins. However, the results of subsequent pharmacological inhibition and protein stability analyses indicated that HIF-1α protein downregulation induced by short-term GS-HCl treatment was not through modulation of the mTOR/p70S6K/S6 signaling pathways, the 26S proteasomal and lysosomal activities and HIF-1α protein stability. Importantly, our further analyses identified that HIF-1α protein downregulation induced by short-term GS-HCl treatment was blunted by exogenous administration of the citric acid cycle metabolites citrate and 2-oxoglutarate, but not the glycolytic end byproducts pyruvate and lactate. These findings demonstrate firstly that short-term GS treatment selectively downregulates HIF-1α at the protein level in YD-8 cells via interference of production of the citric acid cycle metabolites. It is proposed that short-term GS-HCl exposure may be applied for the treatment of oral tumors with high expression of HIF-1α.
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu 704-701, Republic of Korea.
authors.forename: Jeong-Rang
authors.initials: JR
authors.lastname: Jo
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu 704-701, Republic of Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu 704-701, Republic of Korea.
authors.forename: Byeong-Churl
authors.initials: BC
authors.lastname: Jang
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D045744:Cell Line, Tumor; D019343:Citric Acid / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005942:Gluconates / Q000494:pharmacology; D005944:Glucosamine / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014062:Tongue Neoplasms / Q000378:metabolism*
chemical_list: C497396:ARNT protein, human; D005942:Gluconates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007976:Leupeptins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C008229:2-ketogluconate; D019343:Citric Acid; D019344:Lactic Acid; D019289:Pyruvic Acid; D046988:Proteasome Endopeptidase Complex; D005944:Glucosamine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde