cFLIPL prevents TRAIL-induced apoptosis of hepatocellular carcinoma cells by inhibiting the lysosomal pathway of apoptosis

Maria Eugenia Guicciardi, Steven F. Bronk, Nathan W. Werneburg, Gregory J. Gores

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Sensitivity to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and the lysosomal pathway of cell death are features of cancer cells. However, it is unknown if TRAIL cytotoxic signaling engages the lysosomal pathway of cell death. Our aim, therefore, was to ascertain if TRAIL killing involves lysosomal permeabilization. TRAIL-induced apoptosis of hepatocellular carcinoma cells (HuH-7, Hep3B) was associated with lysosomal permeabilization, as demonstrated by redistribution of the lysosomal protease cathepsin B into the cytosol. Pharmacological and short hairpin RNA-targeted inhibition of cathepsin B reduced apoptosis. Because cellular FLICE-inhibitory protein (cFLIP) inhibits TRAIL-induced cell death and is frequently overexpressed by human cancers, the ability of cFLIP to prevent lysosomal permeabilization during TRAIL treatment was examined. Enforced long-form cFLIP (cFLIPL) expression reduced release of cathepsin B from lysosomes and attenuated apoptosis. cFLIP L overexpression was also associated with robust p42/44 MAPK activation following exposure to TRAIL. In contrast, cFLIPL overexpression attenuated p38 MAPK activation and had no significant effect on JNK and NF-κB activation. Inhibition of p42/44 MAPK by PD98059 restored TRAIL-mediated lysosomal permeabilization and apoptosis in cFLIP-overexpressing cells. In conclusion, these results demonstrate that lysosomal permeabilization contributes to TRAIL-induced apoptosis of hepatocellular carcinoma cells and suggest that cFLIPL cytoprotection is, in part, due to p42/44 MAPK-dependent inhibition of lysosomal breakdown.

Original languageEnglish (US)
Pages (from-to)G1337-G1346
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume292
Issue number5
DOIs
StatePublished - May 2007

Keywords

  • Caspase-8
  • Cathepsin B
  • PD98059
  • p42/44 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'cFLIP<sub>L</sub> prevents TRAIL-induced apoptosis of hepatocellular carcinoma cells by inhibiting the lysosomal pathway of apoptosis'. Together they form a unique fingerprint.

  • Cite this