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

35 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

Fingerprint

M Phase Cell Cycle Checkpoints
Mitosis
Flavonoids
Cytokinesis
Aurora Kinase B
Anticarcinogenic Agents
Antimitotic Agents
fisetin
Kinetochores
Chromosome Segregation
Free Radical Scavengers
Centromere
Proteasome Endopeptidase Complex
Wine
Microtubules
Vegetables
Culture Media
Fruit
Cell Survival
Anti-Inflammatory Agents

Keywords

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

Cite this

Salmela, A-L., Pouwels, J., Varis, A., Kukkonen, A., Toivonen, P., Halonen, P., ... 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
Salmela, Anna-Leena ; Pouwels, Jeroen ; Varis, Asta ; Kukkonen, Anu ; Toivonen, Pauliina ; Halonen, Pasi ; Perälä, Merja ; Kallioniemi, Olli ; Gorbsky, Gary J. ; Kallio, Marko. / Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. In: Carcinogenesis. 2009 ; Vol. 30, No. 6. pp. 1032-1040.
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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.",
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author = "Anna-Leena Salmela and Jeroen Pouwels and Asta Varis and Anu Kukkonen and Pauliina Toivonen and Pasi Halonen and Merja Per{\"a}l{\"a} and Olli Kallioniemi and Gorbsky, {Gary J.} and Marko Kallio",
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Salmela, A-L, Pouwels, J, Varis, A, Kukkonen, A, Toivonen, P, Halonen, P, Perälä, M, Kallioniemi, O, Gorbsky, GJ & Kallio, M 2009, 'Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint', Carcinogenesis, vol. 30, no. 6, pp. 1032-1040. https://doi.org/10.1093/carcin/bgp101

Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. / Salmela, Anna-Leena; Pouwels, Jeroen; Varis, Asta; Kukkonen, Anu; Toivonen, Pauliina; Halonen, Pasi; Perälä, Merja; Kallioniemi, Olli; Gorbsky, Gary J.; Kallio, Marko (Corresponding Author).

In: Carcinogenesis, Vol. 30, No. 6, 2009, p. 1032-1040.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint

AU - Salmela, Anna-Leena

AU - Pouwels, Jeroen

AU - Varis, Asta

AU - Kukkonen, Anu

AU - Toivonen, Pauliina

AU - Halonen, Pasi

AU - Perälä, Merja

AU - Kallioniemi, Olli

AU - Gorbsky, Gary J.

AU - Kallio, Marko

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - fisetin

KW - flavonoids

KW - mitosis

KW - anticarcinogenic

KW - antioxidant activity

KW - antioxidants

U2 - 10.1093/carcin/bgp101

DO - 10.1093/carcin/bgp101

M3 - Article

VL - 30

SP - 1032

EP - 1040

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 6

ER -