Ceramide Synthase 6 Is a Novel Target of Methotrexate Mediating Its Antiproliferative Effect in a p53-Dependent Manner

PloS One
Baharan FekryNatalia I Krupenko

Abstract

We previously reported that ceramide synthase 6 (CerS6) is elevated in response to folate stress in cancer cells, leading to enhanced production of C16-ceramide and apoptosis. Antifolate methotrexate (MTX), a drug commonly used in chemotherapy of several types of cancer, is a strong inhibitor of folate metabolism. Here we investigated whether this drug targets CerS6. We observed that CerS6 protein was markedly elevated in several cancer cell lines treated with MTX. In agreement with the enzyme elevation, its product C16-ceramide was also strongly elevated, so as several other ceramide species. The increase in C16-ceramide, however, was eliminated in MTX-treated cells lacking CerS6 through siRNA silencing, while the increase in other ceramides sustained. Furthermore, the siRNA silencing of CerS6 robustly protected A549 lung adenocarcinoma cells from MTX toxicity, while the silencing of another ceramide synthase, CerS4, which was also responsive to folate stress in our previous study, did not interfere with the MTX effect. The rescue effect of CerS6 silencing upon MTX treatment was further confirmed in HCT116 and HepG2 cell lines. Interestingly, CerS6 itself, but not CerS4, induced strong antiproliferative effect in several cance...Continue Reading

References

Sep 1, 1985·The Journal of Clinical Investigation·B A ChabnerJ Jolivet
Aug 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·C J AllegraB A Chabner
Oct 1, 2003·The Journal of Biological Chemistry·Julie L Bronder, Richard G Moran
Aug 3, 2004·Nature Reviews. Cancer·Besim Ogretmen, Yusuf A Hannun
Aug 4, 2004·EMBO Reports·Anthony H Futerman, Yusuf A Hannun
Apr 13, 2005·The Biochemical Journal·Yukiko MizutaniYasuyuki Igarashi
Jul 15, 2005·The Biochemical Journal·Natalia V OleinikSergey A Krupenko
Jun 3, 2006·The Prostate·Marcio C Bajgelman, Bryan E Strauss
Jul 11, 2006·Methods : a Companion to Methods in Enzymology·Jacek BielawskiAlicja Bielawska
Mar 3, 2007·Cancer Metastasis Reviews·Yehuda G Assaraf
Jan 25, 2008·Nature Reviews. Molecular Cell Biology·Yusuf A Hannun, Lina M Obeid
Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Steven W Bailey, June E Ayling
Sep 3, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Can E SenkalBesim Ogretmen
Dec 5, 2009·Best Practice & Research. Clinical Haematology·Joseph R Bertino
Apr 22, 2010·Cellular Signalling·Judith MesicekRichard Kolesnick
Aug 26, 2010·Biochemical Pharmacology·Susanne SchiffmannSabine Grösch
Oct 14, 2010·Journal of Lipid Research·Thomas D MullenLina M Obeid
Dec 15, 2010·The Journal of Biological Chemistry·Sergei A NovgorodovTatyana I Gudz
Apr 24, 2012·Hematology/oncology Clinics of North America·Michele VisentinI David Goldman
Apr 28, 2012·The Journal of Biological Chemistry·Elad L LaviadAnthony H Futerman
Jun 8, 2012·Cancer Biology & Therapy·M Danielle BarefordPaul Dent
Aug 28, 2012·Nature Chemical Biology·R David SentelleBesim Ogretmen
Mar 5, 2013·PloS One·Shankar VaradarajanGerald M Cohen
Mar 23, 2013·The Journal of Biological Chemistry·L Alexis HoeferlinNatalia I Krupenko
Apr 25, 2013·Biochimica Et Biophysica Acta·Rotem Tidhar, Anthony H Futerman
Sep 12, 2013·Biochimica Et Biophysica Acta·Joo-Won ParkAnthony H Futerman
Sep 24, 2013·Biochimica Et Biophysica Acta·Wenhui Jiang, Besim Ogretmen
Feb 19, 2014·Nature Reviews. Rheumatology·Darren PlantAnne Barton
Apr 16, 2014·Nature Reviews. Clinical Oncology·Peter M WilsonRobert D Ladner

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Citations

Nov 18, 2017·Nature Reviews. Cancer·Besim Ogretmen
Dec 7, 2019·Rheumatology·Gabriel Miltenberger-MiltenyiJoão Eurico Fonseca
Jun 17, 2020·FEBS Letters·Woo-Jae Park, Joo-Won Park
Dec 6, 2019·International Journal of Molecular Sciences·Miroslav MachalaJan Vondráček
Jul 8, 2017·Cancer Biology & Therapy·E Ramsay CampChristina Voelkel-Johnson
Jun 16, 2016·The Journal of Biological Chemistry·Baharan FekryNatalia I Krupenko
Oct 10, 2018·Biomolecules·Roger S HolmesNatalia I Krupenko
Aug 24, 2019·Progress in Lipid Research·Sebastian BrachtendorfSabine Grösch
Nov 14, 2020·Experimental Lung Research·Huijiang QianXiao-Dong Lv
Mar 17, 2020·Chemico-biological Interactions·Keri A BarronNatalia I Krupenko
Feb 23, 2019·Chemico-biological Interactions·Sergey A Krupenko, Natalia I Krupenko
Sep 24, 2019·Current Medicinal Chemistry·Petra GrbčićMirela Sedić
Aug 7, 2021·The Journal of Nutritional Biochemistry·Keri BarronNatalia Krupenko
Aug 7, 2021·Medicina·Ana Gomez-LarrauriAlberto Ouro
Nov 23, 2021·Frontiers in Nutrition·Keri BarronNatalia Krupenko

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BETA
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Fiji
GraphPad

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