Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint

Abstract

Fisetin is a natural flavonol present in edible vegetables, fruits and wine at 2-160 microg/g concentrations and an ingredient in nutritional supplements with much higher concentrations. The compound has been reported to exert anticarcinogenic effects as well as antioxidant and anti-inflammatory activity via its ability to act as an inhibitor of cell proliferation and free radical scavenger, respectively. Our cell-based high-throughput screen for small molecules that override chemically induced mitotic arrest identified fisetin as an antimitotic compound. Fisetin rapidly compromised microtubule drug-induced mitotic block in a proteasome-dependent manner in several human cell lines. Moreover, in unperturbed human cancer cells fisetin caused premature initiation of chromosome segregation and exit from mitosis without normal cytokinesis. To understand the molecular mechanism behind these mitotic errors, we analyzed the consequences of fisetin treatment on the localization and phoshorylation of several mitotic proteins. Aurora B, Bub1, BubR1 and Cenp-F rapidly lost their kinetochore/centromere localization and others became dephosphorylated upon addition of fisetin to the culture medium. Finally, we identified Aurora B kinase as a novel direct target of fisetin. The activity of Aurora B was significantly reduced by fisetin in vitro and in cells, an effect that can explain the observed forced mitotic exit, failure of cytokinesis and decreased cell viability. In conclusion, our data propose that fisetin perturbs spindle checkpoint signaling, which may contribute to the antiproliferative effects of the compound.

Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol

“…Geraldol has no known biological activity, but fisetin, a closely structurally related flavonoid that induces mitotic slippage less potently than geraldol ( Supplementary Fig. S3), has also been reported to inhibit Aurora B (30). Geraldol was assayed for in vitro inhibition of a panel of kinases including Src, Aurora A, and Aurora B (Supplementary Table S1) and showed significant inhibition of Aurora A and Aurora B but not Src.…”

“…Our group and others have identified chemicals that stimulate mitotic slippage and observed that slipped cells typically undergo at least 1 round of DNA replication without subsequent cell division but that, eventually, all cells that undergo mitotic slippage die (26)(27)(28)(29)(30) (27), and fisetin (30); Supplementary Fig. S1].…”

Fisetin, a Dietary Flavonoid, Induces Cell Cycle Arrest and Apoptosis through Activation of p53 and Inhibition of NF‐Kappa B Pathways in Bladder Cancer Cells

“…Fisetin (3,3¢,4¢,7-tetrahydroxyflavone) is a natural flavonoid found in the smoke tree and is also widely distributed in various fruits and vegetables such as strawberry, apple, persimmon, grape, onion and cucumber [6]. Fisetin has been reported to exhibit a wide variety of activities, including neurotrophic, antioxidant, anti-inflammatory, antimetastatic and anti-angiogenic effects [7][8][9][10][11]. Moreover, it has been shown to suppress the proliferation and induce apoptosis of a wide variety of tumour cells, including prostate cancer, liver cancer, colon cancer, pancreatic cancer, hepatocellular cancer and leukaemia cells [12][13][14][15][16].…”

In vitro and in vivo characterization of a benzofuran derivative, a potential anticancer agent, as a novel Aurora B kinase inhibitor

“…1H), were found to potently suppress endogenous Aurora B activity [24,25]. Natural product Fisetin and Luteolin were also reported to inhibit Aurora B kinase activity in cancer cells [26,27]. In addition to AZD1152, AT9283, PHA-739358, MLN8237 and ENMD2076 (Fig.…”