NDLI: Ceramide mediates nanovesicle shedding and cell death in response to phosphatidylinositol ether lipid analogs and perifosine.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gills, J. J. Zhang, C. Abu-Asab, M. S. Castillo, S. S. Marceau, C. LoPiccolo, J. Kozikowski, A. P. Tsokos, M. Goldkorn, T. Dennis, P. A.
Description	Country affiliation: United States Author Affiliation: Gills JJ ( Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4254, USA.)
Abstract	Anticancer phospholipids that inhibit Akt such as the alkylphospholipid perifosine (Per) and phosphatidylinositol ether lipid analogs (PIAs) promote cellular detachment and apoptosis and have a similar cytotoxicity profile against cancer cell lines in the NCI60 panel. While investigating the mechanism of Akt inhibition, we found that short-term incubation with these compounds induced rapid shedding of cellular nanovesicles containing EGFR, IGFR and p-Akt that occurred in vitro and in vivo, while prolonged incubation led to cell detachment and death that depended on sphingomyelinase-mediated generation of ceramide. Pretreatment with sphingomyelinase inhibitors blocked ceramide generation, decreases in phospho-Akt, nanovesicle release and cell detachment in response to alkylphospholipids and PIAs in non-small cell lung cancer cell lines. Similarly, exogenous ceramide also decreased active Akt and induced nanovesicle release. Knockdown of neutral sphingomyelinase decreased, whereas overexpression of neutral or acid sphingomyelinase increased cell detachment and death in response to the compounds. When transferred in vitro, PIA or Per-induced nanovesicles increased ceramide levels and death in recipient cells. These results indicate ceramide generation underlies the Akt inhibition and cytotoxicity of this group of agents, and suggests nanovesicle shedding and uptake might potentially propagate their cytotoxicity in vivo.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.72
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-07-05
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Toxicity Research Support, N.i.h., Intramural Transplantation, Heterologous Phosphatidylinositol Phosphates Lung Neoplasms Antagonists & Inhibitors Ceramides Genetics Proto-oncogene Proteins C-akt Pyridines Rna, Small Interfering Drug Therapy Antineoplastic Agents Secretory Vesicles Phosphorylcholine Metabolism Drug Effects Rna Interference Therapeutic Use Discipline Cell Biology Pathology Chemistry Animals Sphingomyelin Phosphodiesterase Mice, Nude Cell Line, Tumor Receptor, Igf Type 1 Mice Analogs & Derivatives Apoptosis Receptor, Epidermal Growth Factor
Content Type	Text
Resource Type	Article

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