Choline kinase alpha inhibition by EB-3D triggers cellular senescence, reduces tumor growth and metastatic dissemination in breast cancer

Elena Mariotto, Giampietro Viola, Roberto Ronca, Luca Persano, Sanja Aveic, Zaver M Bhujwalla, Noriko Mori, Benedetta Accordi, Valentina Serafin, Luisa Carlota López-Cara, Roberta Bortolozzi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number391
JournalCancers
Volume10
Issue number10
DOIs
StatePublished - Oct 22 2018

Keywords

  • Breast cancer
  • Choline kinase α
  • Senescence
  • Small molecules

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Mariotto, E., Viola, G., Ronca, R., Persano, L., Aveic, S., Bhujwalla, Z. M., Mori, N., Accordi, B., Serafin, V., López-Cara, L. C., & Bortolozzi, R. (2018). Choline kinase alpha inhibition by EB-3D triggers cellular senescence, reduces tumor growth and metastatic dissemination in breast cancer. Cancers, 10(10), [391]. https://doi.org/10.3390/cancers10100391