EP1747 - LBA_ECE_1003 - TMC from Glycyrrhiza uralensis suppresses hypoxic tumor microenvironment by co-targeting the HIF-1α–neuroendocrine axis and angiogenic signaling in colorectal cancer
TL;DR
Results suggest that TMC may serve as a potential therapeutic candidate for targeting hypoxia-associated neuroendocrine signaling and angiogenesis, and demonstrates that TMC acts as a multi-target inhibitor that suppresses hypoxia-driven angiogenic signaling while simultaneously modulating the neuroendocrine stress axis involving TH, CRH, and ET-1.
Abstract
Hypoxia is a key feature of the tumor microenvironment that activates hypoxia-inducible factor-1α (HIF-1α), leading to enhanced angiogenesis and dysregulation of neuroendocrine signaling pathways. In this study, we investigated the effects of 3,3′,4,4′-tetrahydroxy-2-methoxychalcone (TMC), a bioactive chalcone isolated from Glycyrrhiza uralensis, on hypoxia-induced angiogenic signaling and neuroendocrine mediator expression. In human colorectal cancer HCT-116 cells, hypoxic exposure markedly increased HIF-1α protein expression, accompanied by elevated vascular endothelial growth factor (VEGF) levels. TMC treatment significantly suppressed hypoxia-induced HIF-1α protein accumulation through a post-translational mechanism and consequently reduced VEGF expression. Notably, hypoxia also significantly increased the mRNA expression of neuroendocrine-related mediators, including tyrosine hydroxylase (TH), corticotropin-releasing hormone (CRH), and endothelin-1 (ET-1). Treatment with TMC significantly reduced these hypoxia-induced increases at higher concentrations, suggesting that TMC may modulate neuroendocrine stress responses under hypoxic conditions. The anti-angiogenic activity of TMC was further evaluated in human umbilical vein endothelial cells (HUVECs), where TMC significantly inhibited VEGF-induced tube formation, wound healing, and invasion. In addition, treatment with TMC in a zebrafish model reduced HIF-1α protein levels without observable developmental or cardiac toxicity. Collectively, these findings demonstrate that TMC acts as a multi-target inhibitor that suppresses hypoxia-driven angiogenic signaling while simultaneously modulating the neuroendocrine stress axis involving TH, CRH, and ET-1. These results suggest that TMC may serve as a potential therapeutic candidate for targeting hypoxia-associated neuroendocrine signaling and angiogenesis.