Forchlorfenuron-Induced Mitochondrial Respiration Inhibition and Metabolic Shifts in Endometrial Cancer

TL;DR: A novel target of FCF is revealed and its downstream signaling events are elucidated, suggesting that FCF may hold promise as a potential therapeutic in endometrial cancer.

Abstract: Simple Summary Our research focuses on the molecular mechanism of forchlorfenuron (FCF), a plant growth regulator widely used in agriculture to enhance fruit size and quality, and explored its potential in cancer treatment. Despite its known effects, the specific cellular and molecular mechanisms behind FCF’s actions have been unclear. Our study reveals a new mechanism: FCF inhibits mitochondrial respiration, affecting crucial cellular energy processes. This discovery sheds light on how FCF connects to the regulation of HIF-1α and glucose uptake observed in previous studies. Our findings not only deepen our understanding of FCF but also hint at the possibility of novel cancer therapies when combined with existing glycolytic inhibitors. Abstract Forchlorfenuron (FCF) is a widely used plant cytokinin that enhances fruit quality and size in agriculture. It also serves as a crucial pharmacological tool for the inhibition of septins. However, the precise target of FCF has not yet been fully determined. This study reveals a novel target of FCF and elucidates its downstream signaling events. FCF significantly impairs mitochondrial respiration and mediates metabolic shift toward glycolysis, thus making cells more vulnerable to glycolysis inhibition. Interestingly, FCF’s impact on mitochondrial function persists, even in cells lacking septins. Furthermore, the impaired mitochondrial function leads to the degradation of HIF-1α, facilitated by increased cellular oxygen. FCF also induces AMPK activation, suppresses Erk1/2 phosphorylation, and reduces the expression of HER2, β-catenin, and PD-L1. Endometrial cancer is characterized by metabolic disorders such as diabetes and aberrant HER2/Ras-Erk1/2/β-catenin signaling. Thus, FCF may hold promise as a potential therapeutic in endometrial cancer.