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

Anna-Leena Salmela, Jeroen Pouwels, Asta Varis, Anu Kukkonen, Pauliina Toivonen, Pasi Halonen, Merja Perälä, Olli Kallioniemi, Gary J. Gorbsky, Marko Kallio (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

36 Citations (Scopus)

Abstract

Fisetin is a natural flavonol present in edible vegetables, fruits and wine at 2–160 μg/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.
Original languageEnglish
Pages (from-to)1032-1040
JournalCarcinogenesis
Volume30
Issue number6
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

Keywords

  • fisetin
  • flavonoids
  • mitosis
  • anticarcinogenic
  • antioxidant activity
  • antioxidants

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    Salmela, A-L., Pouwels, J., Varis, A., Kukkonen, A., Toivonen, P., Halonen, P., Perälä, M., Kallioniemi, O., Gorbsky, G. J., & Kallio, M. (2009). Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis, 30(6), 1032-1040. https://doi.org/10.1093/carcin/bgp101