Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel-Lindau-dependent pathway

Ching Hao Li, Po Lin Liao, Ya Ting Yang, Shih Hsuan Huang, Cheng Hui Lin, Yu Wen Cheng, Jaw Jou Kang

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)659-671
Number of pages13
JournalArchives of Toxicology
Volume88
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • Hypoxia-inducible factor-1 alpha
  • Minocycline
  • Neovasculogenesis
  • Prolyl hydroxylase
  • Von Hippel-Lindau

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis
  • Medicine(all)

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