Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel-Lindau-dependent pathway
Journal
Archives of Toxicology
Journal Volume
88
Journal Issue
3
Pages
659-671
Date Issued
2014
Author(s)
JAW-JOU KANG
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. ? 2013 Springer-Verlag Berlin Heidelberg.
Subjects
Hypoxia-inducible factor-1 alpha; Minocycline; Neovasculogenesis; Prolyl hydroxylase; Von Hippel-Lindau
SDGs
Other Subjects
gelatinase A; glucose transporter 1; HIF1A protein, human; hypoxia inducible factor 1alpha; minocycline; phosphatidylinositol 3 kinase; procollagen proline 2 oxoglutarate 4 dioxygenase; protein kinase B; SLC2A1 protein, human; vasculotropin C; VHL protein, human; von Hippel Lindau protein; cell hypoxia; cell line; cell motion; drug effects; genetics; human; metabolism; Neovascularization, Pathologic; signal transduction; umbilical vein endothelial cell; Cell Hypoxia; Cell Line; Cell Movement; Glucose Transporter Type 1; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 2; Minocycline; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Prolyl Hydroxylases; Proto-Oncogene Proteins c-akt; Signal Transduction; Vascular Endothelial Growth Factor C; Von Hippel-Lindau Tumor Suppressor Protein
Type
journal article