Date Published: January 8, 2010
Publisher: Public Library of Science
Author(s): Josep Maria Lluis, Ulrich Nachbur, Wendy Diane Cook, Ian Edward Gentle, Donia Moujalled, Maryline Moulin, Wendy Wei-Lynn Wong, Nufail Khan, Diep Chau, Bernard Andrew Callus, James Edward Vince, John Silke, David Lawrence Vaux, Andreas Bergmann. http://doi.org/10.1371/journal.pone.0008620
Abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a “death ligand”—a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-κB and JNK signalling pathways. To determine the role of TGF-β-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1−/− MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-κB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-κB, protected TAK1−/− MEFs against TRAIL killing, suggesting that TAK1 activation of NF-κB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-κB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK1−/− MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1–NF-κB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance.
Partial Text: TRAIL is a member of the tumor necrosis factor superfamily that selectively induces apoptosis in a wide variety of cancer cells, while sparing normal cells, highlighting its potential as an agent for cancer therapy. So far, the mechanism for differential TRAIL sensitivity has not been established.
NF-κB and JNK participate in a wide variety of cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation and cell death. Because both induction of NF-κB and JNK activation by TRAIL were abolished in TAK1 deficient MEFs, and this corresponded to an increase in sensitivity to TRAIL induced apoptosis, we wanted to determine the role of these signalling pathways in allowing cell survival in the presence of TRAIL.