RRC ID 45488
Author Molina-Guijarro JM, García C, Macías Á, García-Fernández LF, Moreno C, Reyes F, Martínez-Leal JF, Fernández R, Martínez V, Valenzuela C, Lillo MP, Galmarini CM.
Title Elisidepsin Interacts Directly with Glycosylceramides in the Plasma Membrane of Tumor Cells to Induce Necrotic Cell Death.
Journal PLoS One
Abstract Plasma 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.
Volume 10(10)
Pages e0140782
Published 2015-1-1
DOI 10.1371/journal.pone.0140782
PII PONE-D-15-32563
PMID 26474061
PMC PMC4608773
MeSH Animals Cell Line, Tumor Cell Membrane / metabolism* Cell Membrane / pathology Colorectal Neoplasms / drug therapy Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism* Colorectal Neoplasms / pathology Depsipeptides / pharmacology* Glucosylceramides / genetics Glucosylceramides / metabolism* Humans Melanoma / drug therapy Melanoma / genetics Melanoma / metabolism* Melanoma / pathology Mice Necrosis
IF 2.74
Times Cited 7
Human and Animal Cells B16 melanoma 4A5(RCB0557) GM95(RCB1026)