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

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• 作者：Ching-Hao Li (1) (2)
  Po-Lin Liao (3)
  Ya-Ting Yang (3)
  Shih-Hsuan Huang (3) (4)
  Cheng-Hui Lin (4)
  Yu-Wen Cheng (4) (5)
  Jaw-Jou Kang (3)
  
• 关键词：Minocycline ; Hypoxia ; inducible factor ; 1 alpha ; Prolyl hydroxylase ; von Hippel–Lindau ; Neovasculogenesis
• 刊名：Archives of Toxicology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：88
• 期：3
• 页码：659-671
• 全文大小：1,421 KB
• 作者单位：Ching-Hao Li (1) (2)
  Po-Lin Liao (3)
  Ya-Ting Yang (3)
  Shih-Hsuan Huang (3) (4)
  Cheng-Hui Lin (4)
  Yu-Wen Cheng (4) (5)
  Jaw-Jou Kang (3)
  
  1. Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
  2. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
  3. Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
  4. College of Pharmacy, Taipei Medicine University, Taipei, Taiwan
  5. School of Pharmacy, Taipei Medicine University, 250 Wu-Hsing Street, Taipei, Taiwan
  
• ISSN：1432-0738

文摘

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-?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.