Sphingosine mediates TNF alpha-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells
2012 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 53, no 6, 1134-1143 p.Article in journal (Refereed) Published
Normally, cell proliferation and death are carefully balanced in higher eukaryotes, but one of the most important regulatory mechanisms, apoptosis, is upset in many malignancies, including hepatocellular-derived ones. Therefore, reinforcing cell death often is mandatory in anticancer therapy. We previously reported that a combination of tumor necrosis factor-alpha (TNF) and cycloheximide (CHX) efficiently kill HTC cells, a rat hepatoma line, in an apoptosis-like mode. Death is actively mediated by the lysosomal compartment, although lysosomal ceramide was previously shown not to be directly implicated in this process. In the present study, we show that TNF/CHX increase lysosomal ceramide that is subsequently converted into sphingosine. Although ceramide accumulation does not significantly alter the acidic compartment, the sphingosine therein generated causes lysosomal membrane permeabilization (LMP) followed by relocation of lysosomal cathepsins to the cytoplasm. TNF/CHX-induced LMP is effectively abrogated by siRNAs targeting acid sphingomyelinase or acid ceramidase, which prevent both LMP and death induced by TNF/CHX. Taken together, our results demonstrate that lysosomal accumulation of ceramide is not detrimental per se, whereas its degradation product sphingosine, which has the capacity to induce LMP, appears responsible for the observed apoptotic-like death.-Ullio, C., J. Casas, U. T. Brunk, G. Sala, G. Fabrias, R. Ghidoni, G. Bonelli, F. M. Baccino, and R. Autelli. Sphingosine mediates TNF alpha-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma.
Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology , 2012. Vol. 53, no 6, 1134-1143 p.
ceramide, hepatocellular carcinoma, lysosomes, sphingolipids, tumor necrosis factor-alpha
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-77861DOI: 10.1194/jlr.M022384ISI: 000303913200010OAI: oai:DiVA.org:liu-77861DiVA: diva2:529712
Funding Agencies|Ministero dellUniversita e della Ricerca, Regione Piemonte|SAF2008-00706|Ministerio de Ciencia e Innovacion|SAF2011-22444|2012-05-312012-05-312012-05-31