Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action

Oncogene
A Rodríguez-GonzálezJ C Lacal

Abstract

Choline kinase (ChoK, E.C. 2.7.1.32) is involved in the synthesis of phosphatidylcholine (PC), and has been found to be increased in human tumors and tumor-derived cell lines. Furthermore, ChoK inhibitors have been reported to show a potent and selective antitumoral activity both in vitro and in vivo. Here, we provide the basis for a rational understanding of the antitumoral activity of ChoK inhibitors. In normal cells, blockage of de novo phosphorylcholine (PCho) synthesis by inhibition of ChoK promotes the dephosphorylation of pRb, resulting in a reversible cell cycle arrest at G0/G1 phase. In contrast, ChoK inhibition in tumor cells renders cells unable to arrest in G0/G1 as manifested by a lack of pRb dephosphorylation. Furthermore, tumor cells specifically suffer a drastic wobble in the metabolism of main membrane lipids PC and sphingomyelin (SM). This lipid disruption results in the enlargement of the intracellular levels of ceramides. As a consequence, normal cells remain unaffected, but tumor cells are promoted to apoptosis. Thus, we provide in this study the rationale for the potential clinical use of ChoK inhibitors.

References

Jul 28, 1992·FEBS Letters·A BielawskaY A Hannun
Jul 15, 1990·The Biochemical Journal·M M Billah, J C Anthes
Sep 11, 1986·Nature·W H MoolenaarS W de Laat
Apr 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·O KugeY Akamatsu
Mar 29, 1985·Biochimica Et Biophysica Acta·F UrsiniC Gregolin
Mar 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·J D EskoC R Raetz
Jun 25, 1984·Biochimica Et Biophysica Acta·S L Pelech, D E Vance
Sep 1, 1995·DNA and Cell Biology·J M HudsonM Bar-Eli
Feb 28, 1995·Proceedings of the National Academy of Sciences of the United States of America·G S DbaiboY A Hannun
Jan 1, 1996·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·D N BrindleyD W Waggoner
Jun 1, 1997·Genes & Development·R J SheaffB E Clurman
Jul 18, 1997·Brain Research. Developmental Brain Research·M Q Holmes-McNaryS H Zeisel
Nov 25, 1997·Biochimica Et Biophysica Acta·D E VanceZ Cui
Dec 11, 1997·Oncogene·R Hernández-AlcocebaJ C Lacal
May 23, 1998·The Journal of Biological Chemistry·R U JänickeA G Porter
Mar 17, 1999·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·S HundertmarkV Ragosch
Mar 27, 1999·The Journal of Biological Chemistry·K H Kim, G M Carman
Jul 1, 1999·Genes & Development·C J Sherr, J M Roberts
Sep 29, 2000·Progress in Nucleic Acid Research and Molecular Biology·A Lykidis, S Jackowski
Dec 21, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·T TsukiyamaK Nakayama
Aug 2, 2001·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·C L YenS H Zeisel
Jul 3, 2002·The Journal of Clinical Investigation·Richard Kolesnick

❮ Previous
Next ❯

Citations

Apr 14, 2010·Chemical Reviews·Kristine GlundeZaver M Bhujwalla
Nov 18, 2011·Nature Reviews. Cancer·Kristine GlundeSabrina M Ronen
Jan 1, 2010·Molecular Cancer·Boon Tin ChuaJulian Downward
Dec 5, 2014·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·A Estévez-BraunJ C Lacal
Feb 26, 2008·The International Journal of Biochemistry & Cell Biology·Ana Ramírez de MolinaJuan Carlos Lacal
Mar 10, 2011·NMR in Biomedicine·Franca PodoEgidio Iorio
Jun 19, 2013·NMR in Biomedicine·Noriko MoriZaver M Bhujwalla
Jul 3, 2013·Chembiochem : a European Journal of Chemical Biology·María Sahún-RonceroRamon Hurtado-Guerrero
Apr 22, 2006·Biochimica Et Biophysica Acta·Vinay ChoubeyUday Bandyopadhyay
Apr 14, 2016·Progress in Lipid Research·Sean P ArlauckasE James Delikatny
Apr 16, 2015·Future Medicinal Chemistry·Francisco Fermín Castro-NavasLuisa Carlota López-Cara
Apr 30, 2015·Expert Review of Molecular Diagnostics·Kristine GlundeZaver M Bhujwalla
Jun 9, 2016·Mass Spectrometry Reviews·Raju BanduKwang Pyo Kim
Jul 26, 2018·Future Medicinal Chemistry·Gianluca RubbiniLuisa Carlota López-Cara
Mar 24, 2018·Molecular Medicine Reports·Sharzehan Mohamad Ayub KhanWei Cun See Too
Apr 26, 2006·Molecular Biology Reports·P G UnschuldC B Lücking
Jul 17, 2014·Molecular Cancer Therapeutics·Sean P ArlauckasEdward J Delikatny
Jul 5, 2005·Cancer Research·Ana Ramírez de MolinaJuan Carlos Lacal
Jun 3, 2021·Pharmaceutics·Juan Carlos LacalJoaquín M Campos

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis