TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with potent apoptosis-inducing properties in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as a promising future cancer therapy. Little, however, is known regarding what the role of TRAIL is in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study, we investigated the role of TRAIL in Fas-induced (CD95/Apo-1-induced) hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody-induced hepatocyte apoptosis, liver damage, and associated lethality in vivo. TRAIL enhanced antiFas-induced hepatocyte apoptosis through the activation of JNK and its downstream substrate, the proapoptotic Bcl-2 homolog Bim. Consistently, TRAIL-and Bim-deficient mice and wild-type mice treated with a JNK inhibitor were protected against anti-Fas-induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy.

Increased hepatotoxicity of tumor necrosis factor–related apoptosis-inducing ligand in diseased human liver

“…This view is supported by the recent observation that TRAIL is highly synergistic with CD95L in the induction of hepatocyte apoptosis. 51 Our data in liver explants suggest that TRAIL sensitivity of hepatocytes is not only strongly increased in fatty liver but also in chronic HCV infection. In both diseases apoptosis has been recognized as an important feature of liver injury.…”

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

“…To confirm the specificity of detrimental effects of TRAIL in SCI, we found that the expression of the cell death-related phosphorylated form of kinase JNK was increased 24 h after SCI in spinal cords. Increased phosphorylation of JNK has been reported after treatment with TRAIL in other in vivo and also in in vitro models (Corazza et al, 2006;Jurewicz et al, 2006;Cantarella et al, 2007) and represents a step of the canonical transduction pathway set into motion after binding of TRAIL to its DR5 death receptor (Jaganathan et al, 2002). Thus, it seemed obvious that prevention of TRAIL detrimental effects in SCI by means of TRAILneutralizing antibody was associated with decrease activation of the death-related kinase JNK.…”

Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase–Bim axis and reveals glutathione-S-transferase P1 as Achilles’ heel

“…We have previously identified Bim as an important molecule involved in the crosstalk between the extrinsic and the intrinsic apoptosis pathway. JNK-mediated induction and activation of Bim had a critical role in Fas-and TNF-induced liver damage (Corazza et al, 2006;Kaufmann et al, 2009), chemotherapeutic drug-induced hepatocellular tumor cell apoptosis (Schneider-Jakob et al, 2010), and paracetamol-induced liver damage (Badmann et al, 2011). Thus, JNK-mediated activation of Bim and subsequent engagement of the mitochondrial apoptosis pathway seems to represent a common mechanism how primary and transformed cells are sensitized to apoptosis induction, and thus represent interesting targets of tumor therapy.…”