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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gills, JJ; Zhang, C; Abu-Asab, MS; Castillo, SS; Marceau, C; LoPiccolo, J; Kozikowski, AP; Tsokos, M; Goldkorn, T; Dennis, PA

Published Date

  • July 5, 2012

Published In

Volume / Issue

  • 3 /

Start / End Page

  • e340 -

PubMed ID

  • 22764099

Pubmed Central ID

  • PMC3406576

Electronic International Standard Serial Number (EISSN)

  • 2041-4889

Digital Object Identifier (DOI)

  • 10.1038/cddis.2012.72

Language

  • eng

Conference Location

  • England