Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

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 in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics

“…It also exhibits affinity and specificity for significant cell cycle regulatory molecules, such as CDK6. Upon co-crystallization with CDK6, it was found that fisetin successfully inhibited kinase activity, which is one of the major drivers in cancer [ 40 , 41 ]. Thus, it regulates cell survival and growth as well as cell proliferation by controlling various signaling mechanisms [ 42 ].…”

Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent

“…Fisetin inhibits cell proliferation by targeting the ERK-dependent signaling pathway in astrocytes and gastric cancer [ 14 , 69 ]. In breast cancer cells, fisetin reduces the expression of MMP-9 by inhibiting PKCα/ROS/ERK1/2 and p38 MAPK activation, thereby leading to a decrease in cell migration [ 70 ]. Furthermore, fisetin has been found to regulate MAPK signaling to inhibit cell proliferation and induce apoptosis in acute promyelocytic leukemia cells [ 71 ].…”

Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review

“…Pharmacokinetics and metabolism studies of FIS in vivo have elucidated that geraldol (3,4 ,7-trihydroxy-3 -methoxyflavone) is its active, methoxylated metabolite. It has been shown that it is the only one to locate in the nucleolus, and other structurally similar flavonols do not have such ability [18]. FIS is very hydrophobic in nature, resulting in limited water solubility (<0.8 mg/mL).…”

“…FIS increases the levels of activated caspase-8 [84], -9 and -3 [83] and induces the expression of TNFR-1 and TNFR-2 death receptors, but has no effect on DR-3, -4 and -5, which in association with the protein Bcl-2 and Bax indicate concomitant activation of both external and internal apoptotic pathways [84]. [18] HCC1806, HCC70, HCC1937, BT-549, 20…”