Abstract
The nucleolus of a cell is a critical cellular compartment that is responsible for ribosome biogenesis and plays a central role in tumor progression. Fisetin, a nutraceutical, is a naturally occurring flavonol from the flavonoid group of polyphenols that has anti-cancer effects. Fisetin negatively impacts several signaling pathways that support tumor progression. However, effect of fisetin on the nucleolus and its functions were unknown. We observed that fisetin is able to physically enter the nucleolus. In the nucleolus, RNA polymerase I (RNA Pol I) mediates the biogenesis of ribosomal RNA. Thus, we investigated the impacts of fisetin on the nucleolus. We observed that breast tumor cells treated with fisetin show a 20–30% decreased nucleolar abundance per cell and a 30–60% downregulation of RNA Pol I transcription activity, as well as a 50–70% reduction in nascent rRNA synthesis, depending on the cell line. Our studies show that fisetin negatively influences MAPK/ERK pathway to impair RNA Pol I activity and rRNA biogenesis. Functionally, we demonstrate that fisetin acts synergistically (CI = 0.4) with RNA Pol I inhibitor, BMH-21 and shows a noteworthy negative impact (60% decrease) on lung colonization of breast cancer cells. Overall, our findings highlight the potential of ribosomal RNA (rRNA) biogenesis as a target for secondary prevention and possible treatment of metastatic disease.Fisetin, a natural flavanol, can localize to the nucleolus and decrease rRNA biogenesis. It preferentially targets tumorigenic cells and cells with cancer stem-like properties. In combination with the RNA Pol I inhibitor BMH-21, it synergistically inhibits pulmonary metastasis, making this combination an exciting potential therapeutic strategy.
Highlights
The term “nutraceutical” was first coined by Dr Stephen De Felice in 1989 [1]
We recently demonstrated that triplenegative breast cancer (TNBC) cells are more reliant on elevated ribosomal RNA (rRNA) biogenesis [31]
Fisetin was found to have an emission peak of ~480 nm [16, 39]. These studies were conducted in mouse nerve cells and suggested that fisetin may localize to nucleolus
Summary
The term “nutraceutical” was first coined by Dr Stephen De Felice in 1989 [1]. Nutraceuticals have been used to prevent and/or treat diseases and increase wellness since ancient times. Fisetin modulates the cytoskeletal structure of endothelial cells by increasing microtubule stability and displays antiangiogenic activity [12]. It inhibits the migration of endothelial cells [13]. Touil et al elucidated pharmacokinetics and in vivo metabolism of fisetin [14]. They discovered that geraldol (3,4′,7-trihydroxy-3′-methoxyflavone) is an active, methoxylated metabolite of fisetin (Fig. 1A). Geraldol was found to be more effective at inhibiting angiogenesis than fisetin [14, 15]. Additional studies revealed that other structurally similar flavonols do not localize to the nucleolus, but geraldol, fisetin’s active metabolite does [16]
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