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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Boronic Acids, Bortezomib, Cell Line, Tumor, Chick Embryo, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Synergism, Humans, Mitochondria, Pyrazines, Receptors, Death Domain, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Xenograft Model Antitumor Assays.
user
Does bortezomib prime neuroblastoma cells for TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway? Context: Searching for novel strategies to modulate apoptosis in neuroblastoma, we investigated the potential of the proteasome inhibitor bortezomib. The effect of bortezomib on TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis signaling pathways was analyzed in neuroblastoma cell lines, primary neuroblastoma cultures, and in an in vivo model. Bortezomib synergistically cooperates with TRAIL to induce apoptosis and to reduce colony formation of neuroblastoma cells (combination index: 0.5). Mechanistic studies reveal that bortezomib profoundly enhances TRAIL-induced cleavage of Bid into tBid, accumulation of tBid in the cytosol, and its insertion into mitochondrial membranes, pointing to a concerted effect on Bid cleavage (TRAIL) and stabilization of tBid (bortezomib), which links the death receptor to the mitochondrial pathway. In addition, bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak, loss of the mitochondrial membrane potential, cytochrome c release, caspase activation, and caspase-dependent apoptosis on treatment with bortezomib and TRAIL. Knockdown of Bid, Noxa, or p53 significantly delays the kinetic of bortezomib- and TRAIL-induced apoptosis, whereas it does not confer long-term protection. By comparison, overexpression of Bcl-2, which simultaneously antagonizes tBid and p53, significantly inhibits bortezomib- and TRAIL-induced apoptosis and even rescues clonogenic survival. Importantly, bortezomib and TRAIL act in concert to trigger apoptosis and to suppress tumor growth in patient-derived primary neuroblastoma cells and in an in vivo model of neuroblastoma.
assistant
Bortezomib represents a promising new approach to prime neuroblastoma cells toward TRAIL, which warrants further investigation. Final Decision: yes