4-O-Methylascochlorin, Methylated Derivative of Ascochlorin, Stabilizes HIF-1α via AMPK Activation
Environmental Health Science
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.
Jeong, J., Kang, J. H., Hwang, S., Cho, H., Park, K., Park, Y., et al. (2011). 4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1α via AMPK activation. Biochemical and Biophysical Research Communications, 406(3), 353-358. doi: 10.1016/j.bbrc.2011.02.043
Originally published in Biochemical and Biophysical Research Communications. https://doi.org/10.1016/j.bbrc.2011.02.043