Chloramphenicol induces autophagy and inhibits the hypoxia inducible factor-1 alpha pathway in non-small cell lung cancer cells

Han Lin Hsu, Po Lin Liao, Yu Wen Cheng, Shih Hsuan Huang, Chien Hua Wu, Ching Hao Li, Jaw Jou Kang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Chloramphenicol is an inexpensive and excellent bactericidal antibiotic. It is used to combat anaerobic infections in the Third World countries, whereas its systemic application has been abandoned in developed countries. However, in recent years, clinicians have reintroduced chloramphenicol in clinical practice. In this study, chloramphenicol was found to repress the oxygen-labile transcription factor, hypoxia inducible factor-1 alpha (HIF-1α), in hypoxic A549 and H1299 cells. Furthermore, it suppressed the mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1, eventually decreasing VEGF release. Chloramphenicol initiated the autophagy pathway in treated cells, as observed by the increase in formation of Atg12-Atg5 conjugates, and in beclin-1 and LC3-II levels. The chloramphenicol-mediated HIF-1α degradation was completely reverted by autophagic flux blockage. In HIF-1α-overexpressing cells, the formation of HIF-1α/SENP-1 (Sentrin/SUMO-specific protease 1) protein complex seemed to facilitate the escape of HIF-1α from degradation. Chloramphenicol inhibited HIF-1α/SENP-1 protein interaction, thereby destabilizing HIF-1α protein. The enhancement in HIF-1α degradation due to chloramphenicol was evident during the incubation of the antibiotic before hypoxia and after HIF-1α accumulation. Since HIF-1α plays multiple roles in infections, inflammation, and cancer cell stemness, our findings suggest a potential clinical value of chloramphenicol in the treatment of these conditions.

Original languageEnglish
Article number157
JournalInternational Journal of Molecular Sciences
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Autophagy
  • Chloramphenicol
  • Hypoxia inducible factor-1 alpha
  • SENP-1
  • A549 Cells
  • Sequestosome-1 Protein/metabolism
  • Humans
  • Autophagy/drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Cell Survival/drug effects
  • Carcinoma, Non-Small-Cell Lung/metabolism
  • Vascular Endothelial Growth Factor A/metabolism
  • Cell Hypoxia
  • Lung Neoplasms/metabolism
  • Cell Line, Tumor
  • Protein Binding
  • Beclin-1/metabolism
  • Chloramphenicol/pharmacology
  • Glucose Transporter Type 1/metabolism
  • Cysteine Endopeptidases/metabolism
  • Microtubule-Associated Proteins/metabolism

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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