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Carcinogenesis Advance Access published online on April 24, 2009
Carcinogenesis, doi:10.1093/carcin/bgp101
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Anna-Leena Salmela1,2,*, Jeroen Pouwels1,*, Asta Varis3,*, Anu Kukkonen3, Pauliina Toivonen1, Pasi Halonen1, Merja Perälä1, Olli Kallioniemi1,4, Gary J. Gorbsky5 and Marko J. Kallio1,3,4,#

1 VTT Technical Research Centre of Finland, Medical Biotechnology, 20521 Turku Finland
2 Turku Graduate School of Biomedical Sciences, 20520 Turku, Finland
3 Turku Centre for Biotechnology, University of Turku, 20521 Turku, Finland
4 Centre of Excellence for Translational Genome-Scale Biology, Academy of Finland, Finland
5 Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, MS 48, Oklahoma City, OK, 73104, USA

# To whom correspondence should be addressed: Marko J. Kallio, VTT Medical Biotechnology, Itäinen Pitkäkatu 4C, Pharmacity Bldg, 4th Floor, 20521 Turku, Finland. E-mail: marko.kallio{at}vtt.fi

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 anti-carcinogenic effects as well as anti-oxidant 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 anti-mitotic 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 proposes that fisetin perturbs spindle checkpoint signalling, which may contribute to the anti-proliferative effects of the compound.

* These authors contributed equally to this work.

Received November 26, 2008; revised April 15, 2009; accepted April 17, 2009.


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