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4-O-Methylascochlorin inhibits the prolyl hydroxylation of hypoxia-inducible factor-1α, which is attenuated by

Tetsuya Kondo1, Kenji Takeda1, Ryo Muko1

  • 1Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan.

The Journal of Antibiotics
|February 24, 2019
PubMed

Insights

4-O-Methylascochlorin (MAC) boosts hypoxia-inducible factor (HIF)-1α accumulation in cancer cells by inhibiting prolyl hydroxylation. Ascorbate counteracts this effect, highlighting its role in regulating HIF-1α activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hypoxia-inducible factor (HIF)-1α is a key regulator of cellular response to hypoxia.
  • 4-O-Methylascochlorin (MAC), a derivative of ascochlorin, has been shown to influence HIF-1α levels.

Purpose of the Study:

  • To investigate the effects of MAC on HIF-1α expression and function in human fibrosarcoma HT-1080 cells.
  • To elucidate the mechanism underlying MAC-mediated HIF-1α accumulation and the role of ascorbate.

Main Methods:

  • Treatment of HT-1080 cells with MAC.
  • Analysis of HIF-1α protein and mRNA levels.
  • Assessment of HIF target gene transcriptional activity.
  • Measurement of HIF-1α prolyl hydroxylation.
  • Evaluation of intracellular ascorbate concentrations.

Main Results:

  • MAC promoted HIF-1α protein accumulation without altering mRNA levels.
  • MAC enhanced the transcriptional activity of HIF target genes.
  • Ascorbate attenuated MAC-induced HIF-1α accumulation and transcriptional activity.
  • MAC inhibited HIF-1α prolyl hydroxylation at proline 564, an effect reversed by ascorbate.
  • MAC caused a slight decrease in intracellular ascorbate.

Conclusions:

  • MAC promotes HIF-1α accumulation by inhibiting its prolyl hydroxylation.
  • Ascorbate plays a role in modulating MAC's effect on HIF-1α prolyl hydroxylation.
  • These findings provide insights into the regulation of HIF-1α by MAC and ascorbate in cancer cells.

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