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Title

Elisidepsin interacts directly with glycosylceramides in the plasma membrane of tumor cells to induce necrotic cell death

AuthorsMolina-Guijarro, José M.; García, Carolina ; Macías, Álvaro; García-Fernández, Luis F. ; Moreno, Cristina; Valenzuela, Carmen ; Lillo, M. Pilar
Issue Date2015
PublisherPublic Library of Science
CitationPLoS ONE 10(10): e0140782 (2015)
AbstractPlasma membrane integrity is essential for cell life. Any major break on it immediately induces the death of the affected cell. Different molecules were described as disrupting this cell structure and thus showing antitumor activity. We have previously defined that elisidepsin (Irvalec®, PM02734) inserts and self-organizes in the plasma membrane of tumor cells, inducing a rapid loss of membrane integrity, cell permeabilization and necrotic death. Here we show that, in sensitive HCT-116 colorectal cells, all these effects are consequence of the interaction of elisidepsin with glycosylceramides in the cell membrane. Of note, an elisidepsin-resistant subline (HCT-116-Irv) presented reduced levels of glycosylceramides and no accumulation of elisidepsin in the plasma membrane. Consequently, drug treatment did not induce the characteristic necrotic cell death. Furthermore, GM95, a mutant derivative from B16 mouse melanoma cells lacking ceramide glucosyltransferase (UGCG) activity and thus the synthesis of glycosylceramides, was also resistant to elisidepsin. Over-expression of UGCG gene in these deficient cells restored glycosylceramides synthesis, rendering them sensitive to elisidepsin, at a similar level than parental B16 cells. These results indicate that glycosylceramides act as membrane targets of elisidepsin, facilitating its insertion in the plasma membrane and the subsequent membrane permeabilization that leads to drug-induced cell death. They also indicate that cell membrane lipids are a plausible target for antineoplastic therapy.
DescriptionThis is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al.
Publisher version (URL)https://doi.org//10.1371/journal.pone.0140782
URIhttp://hdl.handle.net/10261/130624
DOI10.1371/journal.pone.0140782
Identifiersdoi: 10.1371/journal.pone.0140782
issn: 1932-6203
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