New Pathway Inhibits TRAIL Apoptosis in Glioblastomas

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New Pathway Inhibits TRAIL Apoptosis in Glioblastomas
New Pathway Inhibits TRAIL Apoptosis in Glioblastomas

WEDNESDAY, Jan. 25 (HealthDay News) -- An A20 ligase mediates ubiquitination to inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioblastoma cells, according to an experimental study published online Jan. 24 in Cancer Discovery.

Anita C. Bellail, from Emory University in Atlanta, and colleagues investigated the signaling complexes involved in the inhibition of TRAIL-induced apoptosis in glioblastoma cells.

The researchers found that under physiologic conditions, A20 formed a plasma membrane-bound preligand assembly complex, together with death receptor 5 and receptor interacting protein 1 (RIP1). Caspase-8 was recruited to the plasma membrane-bound preligand assembly complex by treatment with TRAIL, and was involved in assembly of a death-inducing signaling complex. Within this complex, the C-terminal zinc finger of the A20 ubiquitin ligase mediated RIP1 polyubiquitination. The resulting polyubiquitin chains binded to caspase-8 and inhibited its dimerization, cleavage, and subsequent initiation of TRAIL-induced apoptosis. This process occured in glioblastoma-derived cell lines and tumor-initiating cells.

"In conclusion, the data presented here suggest that A20 E3 ligase acts as an oncogene that inhibits TRAIL-induced apoptosis. Targeting of the A20-mediated RIP1 ubiquitination process may therefore lead to the development of combination therapies that can eliminate TRAIL resistance in tumor-initiating cells and enhance the therapeutic efficacy of TRAIL-targeted therapies in human glioblastomas," the authors write.

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