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 anti-cancer therapy. We previously reported that a combination of TNF and 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. While 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, while its degradation product sphingosine, which has the capacity to induce LMP, appears responsible for the observed apoptotic-like death.

Sphingosine mediates TNFalpha-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells

ULLIO, CHIARA;BONELLI, Gabriella;BACCINO, Francesco Maria;AUTELLI, Riccardo
2012-01-01

Abstract

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 anti-cancer therapy. We previously reported that a combination of TNF and 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. While 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, while its degradation product sphingosine, which has the capacity to induce LMP, appears responsible for the observed apoptotic-like death.
2012
53
1134
1143
cell death; ceramide; hepatocellular carcinoma; lysosomes; sphingolipids; sphingosine
Chiara Ullio; Josefina Casas; Ulf T. Brunk; Giuseppina Sala; Gemma Fabriàs; Riccardo Ghidoni; Gabriella Bonelli; Francesco M. Baccino; Riccardo Autel...espandi
File in questo prodotto:
File Dimensione Formato  
2012_Ullio et al_J Lipid Res 53_1134-1143.pdf

Accesso aperto

Descrizione: PDF editoriale
Tipo di file: PDF EDITORIALE
Dimensione 1.38 MB
Formato Adobe PDF
1.38 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/98998
Citazioni
  • ???jsp.display-item.citation.pmc??? 29
  • Scopus 64
  • ???jsp.display-item.citation.isi??? 56
social impact