135 research outputs found
NF-κB Inhibition Reveals Differential Mechanisms of TNF Versus TRAIL-Induced Apoptosis Upstream or at the Level of Caspase-8 Activation Independent of cIAP2
No full textDeath ligands not only activate a death program but also regulate inflammatory signalling pathways, for example, through NF-κB induction. Although tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF both activate NF-κB in human keratinocytes, only TRAIL potently induces apoptosis. However, when induction of NF-κB was inhibited with a kinase dead IKK2 mutant (IKK2-KD), TNF- but not TRAIL-induced apoptosis was dramatically enhanced. Acquired susceptibility to TNF-induced apoptosis was due to increased caspase-8 activation. To investigate the mechanism of resistance of HaCaT keratinocytes to TNF-induced apoptosis, we analyzed a panel of NF-κB-regulated effector molecules. Interestingly, the inhibitor of apoptosis protein (IAP) family member cIAP2, but not cIAP1, X-linked inhibitor of apoptosis, TNF receptor-associated factor (TRAF)-1, or TRAF2, was downregulated in sensitive but not in resistant HaCaT keratinocytes. Surprisingly, however, stable inducible expression of cIAP2 was not sufficient to render IKK2-KD-sensitized keratinocytes resistant to TNF, and reduction of cIAP2 alone did not increase the sensitivity of HaCaT keratinocytes to TNF. In conclusion, we demonstrate that inhibition of NF-κB dramatically sensitizes human keratinocytes to TNF- but not to TRAIL-induced apoptosis and that this sensitization for TNF was largely independent of cIAP2. Our data thus clearly exclude the candidates proposed to date to confer TNF apoptosis resistance and suggest the function of an unanticipated effector of NF-κB critical for the survival of HaCaT keratinocytes upstream or at the level of caspase-8 activation
“Bak (and Bax) to the Future” — of Primary Melanoma Prognosis?
No full textBcl-2 proteins either block or activate the “intrinsic” mitochondrial apoptosis pathway. Loss of expression of proapoptotic Bcl-2 proteins, namely Bax and Bak, in primary melanomas is associated with a worse long-term prognosis. Consequently, inactivation of mitochondrial signaling pathways of apoptosis may not only be a prerequisite for melanoma progression but may also hamper therapeutic efforts with chemotherapeutic drugs
CD95-Mediated Signals in the Skin: Going Out with an (Inflammatory) Bang?
No full textThe death ligand CD95L (Fas/Apo-1–ligand) has been viewed as a proapoptotic molecule involved in the pathogenesis of T cell-mediated skin diseases including eczema. In the presence of inhibitors of caspases, CD95L induces proinflammatory genes in keratinocytes. This more pleiotropic function of CD95L as enhancer of inflammation may be equally important to apoptosis induction of keratinocytes, at least in eczema
Guiding the Killer and Bringing in Accomplices: Bispecific Antibody Treatment for Malignant Melanoma
No full textDiscovery of oncogene and immune checkpoint targeting has transformed melanoma therapy in the last 5 years. However, treatment of primary or secondary drug-resistant melanoma remains a challenge. Agents designed to activate the cell death machinery directly, for example by activating the death receptors expressed by melanoma cells, could break drug resistance, and they may achieve long-lasting therapeutic success. He et al. report their studies of an MCSPxDR5 bispecific, tetravalent antibody that can simultaneously target death receptor 5 (DR5, TRAIL-R2) and melanoma-associated chondroitin sulfate proteoglycan (MCSP). This antibody can exert strong and selective DR5-dependent cytotoxic activity against MCSP-expressing melanoma cells. Crosslinking of the antibody with Fcg-receptors increased the cytotoxic potential further, without compromising its selectivity. This approach offers a novel immunotherapeutic tool via coupling of three cooperating processes: delivering the death receptor agonist to the malignant cell population, potent activation of DR5-mediated cell death signaling, and recruitment of Fcg-receptor-carrying immune cells that can mount an immune response against the tumor cells.peer-reviewe
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