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Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer

Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of s...

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Autores principales: Mariotto, Elena, Viola, Giampietro, Ronca, Roberto, Persano, Luca, Aveic, Sanja, Bhujwalla, Zaver M., Mori, Noriko, Accordi, Benedetta, Serafin, Valentina, López-Cara, Luisa Carlota, Bortolozzi, Roberta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209942/
https://www.ncbi.nlm.nih.gov/pubmed/30360374
http://dx.doi.org/10.3390/cancers10100391
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author Mariotto, Elena
Viola, Giampietro
Ronca, Roberto
Persano, Luca
Aveic, Sanja
Bhujwalla, Zaver M.
Mori, Noriko
Accordi, Benedetta
Serafin, Valentina
López-Cara, Luisa Carlota
Bortolozzi, Roberta
author_facet Mariotto, Elena
Viola, Giampietro
Ronca, Roberto
Persano, Luca
Aveic, Sanja
Bhujwalla, Zaver M.
Mori, Noriko
Accordi, Benedetta
Serafin, Valentina
López-Cara, Luisa Carlota
Bortolozzi, Roberta
author_sort Mariotto, Elena
collection PubMed
description Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer treatment protocols.
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spelling pubmed-62099422018-11-02 Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer Mariotto, Elena Viola, Giampietro Ronca, Roberto Persano, Luca Aveic, Sanja Bhujwalla, Zaver M. Mori, Noriko Accordi, Benedetta Serafin, Valentina López-Cara, Luisa Carlota Bortolozzi, Roberta Cancers (Basel) Article Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer treatment protocols. MDPI 2018-10-22 /pmc/articles/PMC6209942/ /pubmed/30360374 http://dx.doi.org/10.3390/cancers10100391 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mariotto, Elena
Viola, Giampietro
Ronca, Roberto
Persano, Luca
Aveic, Sanja
Bhujwalla, Zaver M.
Mori, Noriko
Accordi, Benedetta
Serafin, Valentina
López-Cara, Luisa Carlota
Bortolozzi, Roberta
Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title_full Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title_fullStr Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title_full_unstemmed Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title_short Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
title_sort choline kinase alpha inhibition by eb-3d triggers cellular senescence, reduces tumor growth and metastatic dissemination in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209942/
https://www.ncbi.nlm.nih.gov/pubmed/30360374
http://dx.doi.org/10.3390/cancers10100391
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