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Molecular Pharmacology

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Fluorizoline blocks theinteraction between prohibitin-2 and γ-glutamylcyclotransferase,and induces p21Waf1/Cip1expression in MCF7 breast cancer cells

Hiroko Takagi, Chiami Moyama, Keiko Taniguchi, Kota Ando, Ryohei Matsuda, Shota Ando, Hiromi Ii, Susumu Kageyama, Akihiro Kawauchi, Nora Chouha, Laurent Désaubry and Susumu Nakata
Molecular Pharmacology December 3, 2021, MOLPHARM-AR-2021-000334; DOI: https://doi.org/10.1124/molpharm.121.000334
Hiroko Takagi
1Kyoto Pharmaceutical University, Japan
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Chiami Moyama
1Kyoto Pharmaceutical University, Japan
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Keiko Taniguchi
1Kyoto Pharmaceutical University, Japan
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Kota Ando
1Kyoto Pharmaceutical University, Japan
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Ryohei Matsuda
1Kyoto Pharmaceutical University, Japan
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Shota Ando
1Kyoto Pharmaceutical University, Japan
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Hiromi Ii
1Kyoto Pharmaceutical University, Japan
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Susumu Kageyama
2Shiga University of Medical Science, Japan
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Akihiro Kawauchi
2Shiga University of Medical Science, Japan
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Nora Chouha
3University of Batna, Algeria
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Laurent Désaubry
4INSERM-University of Strasbourg, France
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Susumu Nakata
5Department of Clinical Oncology, Kyoto Pharmaceutical University, Japan
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  • For correspondence: snakata@mb.kyoto-phu.ac.jp
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Abstract

Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21Waf1/Cip(p21) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines,including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into theDNA synthesis phase.Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline, and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins, and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells.

Significance Statement This study shows that fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins that regulates p21 expression.

  • breast cancer
  • cell cycle
  • glioblastoma cells
  • Prostate cancer
  • tumor suppressor genes
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Fluorizoline induces p21 via PHB2-GGCT interaction blockade

Hiroko Takagi, Chiami Moyama, Keiko Taniguchi, Kota Ando, Ryohei Matsuda, Shota Ando, Hiromi Ii, Susumu Kageyama, Akihiro Kawauchi, Nora Chouha, Laurent Désaubry and Susumu Nakata
Molecular Pharmacology December 3, 2021, MOLPHARM-AR-2021-000334; DOI: https://doi.org/10.1124/molpharm.121.000334

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OtherArticle

Fluorizoline induces p21 via PHB2-GGCT interaction blockade

Hiroko Takagi, Chiami Moyama, Keiko Taniguchi, Kota Ando, Ryohei Matsuda, Shota Ando, Hiromi Ii, Susumu Kageyama, Akihiro Kawauchi, Nora Chouha, Laurent Désaubry and Susumu Nakata
Molecular Pharmacology December 3, 2021, MOLPHARM-AR-2021-000334; DOI: https://doi.org/10.1124/molpharm.121.000334
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