The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

Anna-Leena Salmela, Jeroen Pouwels, Anu Kukkonen-Macchi, Sinikka Waris, Pauliina Toivonen, Kimmo Jaakkola, Jenni Mäki-Jouppila, Lila Kallio (Corresponding Author), Marko J. Kallio

Research output: Contribution to journalArticleScientificpeer-review

14 Citations (Scopus)

Abstract

The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule–kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule–kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

Original languageEnglish
Pages (from-to)578-592
JournalExperimental Cell Research
Volume318
Issue number5
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

M Phase Cell Cycle Checkpoints
Polyploidy
Flavonoids
Apoptosis
Aurora Kinase B
Chromosomes
Anaphase
Cytokinesis
Phytochemicals
Aneuploidy
Mitosis
Microtubules
Cell Division
Libraries
eupatorin
Neoplasms
Carcinogenesis
Cell Death
Cell Culture Techniques
Maintenance

Keywords

  • Aurora B kinase
  • spindle assembly checkpoint
  • mitosis
  • cytokinesis
  • flavonoid
  • eupatorin

Cite this

Salmela, A-L., Pouwels, J., Kukkonen-Macchi, A., Waris, S., Toivonen, P., Jaakkola, K., ... Kallio, M. J. (2012). The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis. Experimental Cell Research, 318(5), 578-592. https://doi.org/10.1016/j.yexcr.2011.12.014
Salmela, Anna-Leena ; Pouwels, Jeroen ; Kukkonen-Macchi, Anu ; Waris, Sinikka ; Toivonen, Pauliina ; Jaakkola, Kimmo ; Mäki-Jouppila, Jenni ; Kallio, Lila ; Kallio, Marko J. / The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis. In: Experimental Cell Research. 2012 ; Vol. 318, No. 5. pp. 578-592.
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abstract = "The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule–kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule–kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.",
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Salmela, A-L, Pouwels, J, Kukkonen-Macchi, A, Waris, S, Toivonen, P, Jaakkola, K, Mäki-Jouppila, J, Kallio, L & Kallio, MJ 2012, 'The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis', Experimental Cell Research, vol. 318, no. 5, pp. 578-592. https://doi.org/10.1016/j.yexcr.2011.12.014

The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis. / Salmela, Anna-Leena; Pouwels, Jeroen; Kukkonen-Macchi, Anu; Waris, Sinikka; Toivonen, Pauliina; Jaakkola, Kimmo; Mäki-Jouppila, Jenni; Kallio, Lila (Corresponding Author); Kallio, Marko J.

In: Experimental Cell Research, Vol. 318, No. 5, 2012, p. 578-592.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

AU - Salmela, Anna-Leena

AU - Pouwels, Jeroen

AU - Kukkonen-Macchi, Anu

AU - Waris, Sinikka

AU - Toivonen, Pauliina

AU - Jaakkola, Kimmo

AU - Mäki-Jouppila, Jenni

AU - Kallio, Lila

AU - Kallio, Marko J.

PY - 2012

Y1 - 2012

N2 - The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule–kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule–kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

AB - The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule–kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule–kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

KW - Aurora B kinase

KW - spindle assembly checkpoint

KW - mitosis

KW - cytokinesis

KW - flavonoid

KW - eupatorin

U2 - 10.1016/j.yexcr.2011.12.014

DO - 10.1016/j.yexcr.2011.12.014

M3 - Article

VL - 318

SP - 578

EP - 592

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

IS - 5

ER -