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Published on: August 6, 2020
4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1α via AMPK activation
Ji-Hak Jeong1, Jeong Han Kang, Seung-Lark Hwang
1Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Abstract:
Chemopreventive or anticancer agents induce cancer cells to apoptosis through the activation of adenosine AMP-activated protein kinase (AMPK), which plays a major role as energy sensors under ATP-deprived condition or ROS generation. In this study, we compared the effects of ascochlorin (ASC), from the fungus Ascochyta viciae, and its derivatives on AMPK activity. We also examined a regulatory mechanism for hypoxia-inducible factor-1α (HIF-1α) stabilization in response to 4-O-methylascochlorin (MAC). We found that AMPK activation was mainly involved with MAC, but not ASC and 4-O-carboxymethylascochlorin (AS-6), indicating that the substitution of 4-O-methyl group from 4-O-hydroxyl group of ASC is important in the activation of AMPK and the expression of HIF-1α. MAC-stabilized HIF-1α via AMPK activation triggered by lowering the intracellular ATP level, not by ROS generation, increases glucose uptake and the expression of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), major target genes of HIF-1α. Moreover, MAC-induced AMPK activity suppressed survival factors, including mTOR and ERK1/2 or translational regulators, including p70S6K and 4E-BP1. Our data suggest that AMPK is a key determinant of MAC-induced HIF-1α expression in response to energy stress, further implying its involvement in MAC-induced apoptosis.
Insights
4-O-methylascochlorin (MAC) activates adenosine AMP-activated protein kinase (AMPK), leading to hypoxia-inducible factor-1α (HIF-1α) stabilization and increased glucose uptake. This mechanism is crucial for MAC-induced cancer cell apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Adenosine AMP-activated protein kinase (AMPK) acts as an energy sensor, crucial for cellular response to energy deprivation and reactive oxygen species (ROS).
- Chemopreventive and anticancer agents often induce apoptosis in cancer cells via AMPK activation.
- Ascochlorin (ASC) is a compound from the fungus Ascochyta viciae with potential anticancer properties.
Purpose of the Study:
- To compare the effects of ascochlorin (ASC) and its derivatives on AMPK activity.
- To investigate the mechanism of hypoxia-inducible factor-1α (HIF-1α) stabilization by 4-O-methylascochlorin (MAC).
- To elucidate the role of AMPK in MAC-induced cellular responses.
Main Methods:
- Comparative analysis of ASC, 4-O-methylascochlorin (MAC), and 4-O-carboxymethylascochlorin (AS-6) on AMPK activation.
- Examination of HIF-1α stabilization mechanisms in response to MAC treatment.
- Assessment of intracellular ATP levels and ROS generation.
- Measurement of glucose uptake, VEGF, and GLUT-1 expression.
- Analysis of survival factors (mTOR, ERK1/2) and translational regulators (p70S6K, 4E-BP1).
Main Results:
- MAC significantly activated AMPK, whereas ASC and AS-6 did not, highlighting the importance of the 4-O-methyl group.
- MAC-induced AMPK activation led to HIF-1α stabilization by reducing intracellular ATP, not by ROS generation.
- Stabilized HIF-1α increased glucose uptake and expression of target genes VEGF and GLUT-1.
- MAC suppressed key survival and translational regulatory pathways, including mTOR, ERK1/2, p70S6K, and 4E-BP1.
Conclusions:
- AMPK activation is critical for MAC-induced HIF-1α expression and subsequent cellular effects.
- The 4-O-methyl group substitution is essential for MAC's ability to activate AMPK and influence HIF-1α.
- MAC's mechanism involves energy stress-induced AMPK activation, leading to apoptosis, suggesting its potential as an anticancer agent.
