title: Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel-Lindau-dependent pathway.
abstract: Hypoxia-mediated stress responses are important in tumor progression, especially when tumor growth causes the tumor to become deprived of its blood supply. The oxygen-labile transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in regulating hypoxia stress-related gene expression and is considered a novel therapeutic target. Lung adenocarcinoma cell lines were exposed to minocycline, followed by incubation at hypoxic condition for 3-6 h. Here, we show that minocycline, a second-generation tetracycline, can induce HIF-1α proteasomal degradation under hypoxia by increasing the expression prolyl hydroxylase-2 and HIF-1α/von Hippel-Lindau protein interaction, thereby overcoming hypoxia-induced HIF-1α stabilization. Neither repression of hypoxia-induced phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway nor inhibition of Hsp90 was required for minocycline-induced HIF-1α degradation. The HIF-1α degradation-enhancing effect of minocycline was evident in both cancerous and primary cells. Minocycline-pretreated, hypoxia-conditioned cells showed a clear reduction in hypoxia response element reporter expression and amelioration of vascular endothelial growth factor C/D (VEGF-C/D), matrix metalloproteinase 2, and glucose transporter 1 expression. By decreasing VEGF secretion of cancerous cells, minocycline could suppress endothelial cell neovasculogenesis. These findings suggest a novel application of minocycline in the treatment of tumor angiogenesis as well as hypoxia-related diseases.
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ching-Hao
authors.initials: CH
authors.lastname: Li
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Liao
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Yang
authors.forename: Shih-Hsuan
authors.initials: SH
authors.lastname: Huang
authors.forename: Cheng-Hui
authors.initials: CH
authors.lastname: Lin
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: Jaw-Jou
authors.initials: JJ
authors.lastname: Kang
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008911:Minocycline / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495677:SLC2A1 protein, human; D042582:Vascular Endothelial Growth Factor C; D064828:Prolyl Hydroxylases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; C497446:VHL protein, human; D008911:Minocycline