Yunping Fan, Department of ENT, head and neck, Oral and Maxillofacial Surgery, Fifth Affiliated Hospital of Sun Yat‐sen University, Guangdong, Zhuhai, China. 1C). Despite the growing interest and successful clinical use of targeted therapies for various malignancies, the precise mechanistic pathway responsible for triggering apoptosis in human tumor cells has lagged behind drug development ( 5). 29). Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. 8C). These findings open the door for new therapeutic strategies targeting a NOXA-mediated apoptotic killing of cancer cells present in patients with melanoma and myeloma. 25). 23) as previously described for C8161 cells ( 27, Although metastatic melanoma cells are notoriously difficult to kill using conventional chemotherapeutic agents, exposure of relatively early passage melanoma cell lines to proteasome inhibitors triggered rapid and substantial apoptosis in vitro and in vivo. Fig. B220+ (yellow) and PNA+ (purple) cells were stained.
The Mcl-1S levels increased following bortezomib exposure, with variable responses for the other Bcl-2 family members. Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Fig. 2). 15 More recently we demonstrated that Noxa … Please log in. The mice were housed at the University of Illinois; Chicago Institutional Animal Care and Use Committee approved the experimental protocol.
Using protein lysates derived from C8161 cells before and after bortezomib exposure in Fig. The pan-caspase inhibitor led to a significant reduction compared with absence of inhibitor (*, P < 0.05) in the bortezomib-induced apoptotic response, but did not reduce the apoptosis to baseline levels, indicating a non-caspase-dependent pathway. 43). and M.A.N. 2, inset). (A) Representative FACS plots of activated B cells. 12). Defining the mechanism of apoptotic action for proteasome inhibitors has been previously elusive, and the current results clearly highlight a key role for NOXA in triggering apoptosis in melanoma and myeloma cells. B and C, proliferating RJ002L (B) and C8161 (C) melanoma cells were subjected to a mitochondrial isolation procedure before and after various time intervals following exposure to bortezomib (1 μmol/L). Normalization for differences in background staining between GC and FB cells was applied, based on signal within the PE− cells. Felix M. Wensveen, Ingrid A. M. Derks, Klaas P. J. M. van Gisbergen, Alex M. de Bruin, Joost C. M. Meijers, HaciAli Yigittop, Martijn A. Nolte, Eric Eldering, René A. W. van Lier; BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation. 36).
Antitumor activity of bortezomib using melanoma xenograft model in vivo. Taking advantage: high-affinity B cells in the germinal center have lower death rates, but similar rates of division, compared to low-affinity cells. Memory B-cell persistence is independent of persisting immunizing antigen. FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen. Fig. 2, right).
I have read and accept the Wiley Online Library Terms and Conditions of Use. Two well-characterized apoptotic pathways involve either engagement of cell surface death receptors with activation of an intracellular cascade of death-inducing proteases such as caspases or a more direct disruption of the mitochondrial membrane potential ( 9). 1B and C), the induction of NOXA following exposure to bortezomib (1 μmol/L) was delayed and accompanied by a less complete activation of the apoptotic machinery as noted for caspases 9, 3, and 8 and poly(ADP)-ribose polymerase ( Proliferation assays were conducted in the presence or absence of 10% FCS by manual counting of melanoma cells in triplicate wells on days 0, 1, 2, and 3. Targeting molecular pathways that regulate diverse cellular responses has emerged as a promising therapeutic strategy ( Fig. Noxa ablation results in survival of multiple B cell clones after immunization. The findings of this study indicate that Noxa, activated transcriptionally by p53, suppress the progression of ACC, whereby it regulates proliferation, apoptosis, and autophagy. Induction of NOXA in melanoma cells occurred at both the mRNA and protein level. It seems counterintuitive that low-affinity cells should contribute to memory. The primer sequences used for NOXA were forward: 5′-AGATGCCTGGGAAGAAG-3′ and reverse: 5′-AGTCCCCTCATGCAAGT-3′ as previously described ( codeveloped and tested the murine MLPA probes; J.C.M.M. However, when caspase-3 activity was assessed, a modest but significant reduction in the number of cells, which stained positive for this apoptosis marker was observed in germinal centers, but not follicular B cells especially of the spleens of Noxa−/− animals (Figure 3Di-ii). Malignancies such as melanoma and multiple myeloma are characterized by aberrant cellular responses to signals governing proliferation and apoptosis. Moreover, the transcriptional activity of NOXA gene could be enhanced by p53. Fig. Conflict-of-interest disclosure: The authors declare no competing financial interests. 57). (ii) Quantifications of B-cell subsets with active caspase-3 (n = 3-8 per genotype; 1 of 2 independent experiments with similar results is shown). We chose to further investigate Noxa, because the ablation of Noxa alters the selection process of antigen-reactive T cells, and moreover conditional deletion of its antagonist Mcl-1 in B cells blocks GC formation and memory B-cell generation.17. Phylogenetic trees were then constructed by applying the Neighbor Joining Method18 to the distance matrix. In a melanoma cell line (C8161), Western blotting confirmed prominent overexpression of FADD DN protein when comparing empty linker with FADD DN–infected cells (Supplementary Fig.
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