Ganoderic acid A targets IL-1R1 and disrupts IL-1β binding in human cancer cells

Abstract

Interleukin 1 (IL-1)-mediated tumor microenvironmental inflammation plays a significant role in cancer development. Despite the recognition of interleukin-1β (IL-1β) and its receptor interleukin-1 receptor 1 (IL-1R1) as crucial targets for cancer treatment, their inhibitors have shown limited efficacy in clinical trials. Ganoderma lucidum, a traditional Chinese medicine known for its health benefits, longevity promotion, and anti-cancer properties, has gained attention. Ganoderic acid A (GAA), a naturally occurring triterpene in Ganoderma lucidum, possesses anti-inflammatory and anti-cancer activities. However, its anti-inflammatory role in the tumor microenvironment is still elusive. To address this, we investigated the interaction of GAA to IL-1β and IL-1R1, and its impact on the binding of IL-1β to IL-R1 in human cancer cells. The research utilized molecular docking, molecular dynamics (MD) simulation, differential scanning fluorimetry (DSF), cytotoxicity assays, caspase 3 activity, and immunofluorescence assays. The results revealed that the GAA could bind and stabilize the trajectory of IL-1R1 at domains 1 and 2. GAA thermally stabilized IL-1R1 and inhibited the viability of A549 and HeLa cells in a dose-dependent manner. Furthermore, GAA exhibited apoptotic activity and significantly inhibited the binding of IL-1β to IL-1R1 in cancer cells. These findings shed new light on the interaction between GAA and interleukins, providing insights into the development of novel natural inhibitors for targeting the inflammatory tumor microenvironment (TME).