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PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The activation status of the three sensors of the UPR pathways (ATF6, IRE1α, and PERK) was measured in the cell line panel shown in Fig. 4A. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Western blot analysis showed that GIST cells exclusively and constitutively expressed the cleaved form of ATF6 (cATF6), which is a transcriptional activator that upregulates the expression of chaperones and cell survival-related genes (Fig. 4A). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | ICC analysis further showed that cATF6 was localized in the nucleus of GIST cells, whereas no nuclear fluorescence signal was detected in other cancer cells (Fig. 4B). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | These results suggest that GISTs may take advantage of ATF6 activation as a survival strategy against various cellular stressors. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Fig. 4GISTs intrinsically adapt to ER stress in an ATF6-dependent manner, which is beneficial for folding and overexpression of MT-KIT.A Activation status of the three arms of the unfolded protein response (UPR) pathway (ATF6, IRE1α, and PERK) was measured by western blotting in a panel of cancer cell lines expressing WT-KIT or MT-KIT. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | B Confocal microscopy was performed to evaluate the nuclear localization of ATF6 in various cancer cell lines selected from the cell line panel used in A. C Cell viability was measured in GIST cells treated with various doses (0.1–5 µM) of an ER-stress inducer, thapsigargin (TG) for 24 h. D GIST cells were treated with 5 µM TG (strong ER-stressor) across various timepoints, and the expression of the three arms of the UPR pathway, a cell-death marker (CHOP), and KIT was measured by western blotting. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | E GIST cells were treated with 0.1 µM TG (mild ER-stressor) across various timepoints, and the expression of the markers measured in D and chaperones (HSP70, HSP90, BIP, and GRP94) was measured by western blotting. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | F Expression of ATF6 and chaperones was measured by western blotting after treatment with 30 µM PF429242 (PF), which blocks ATF6 cleavage. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | G Cell viability of GIST cells treated with 0.1 µM TG and PF was measured after 24 and 48 h. H Immunoprecipitation of GIST cell lysates was performed with a control IgG or KIT antibody, and western blotting was performed against chaperones. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Error bars in C and G represent the SD of the mean of three independent experiments. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | One-way ANOVA with a post-hoc test was performed to compare multiple means (*p < 0.05, **p < 0.01, ***p < 0.001). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | A Activation status of the three arms of the unfolded protein response (UPR) pathway (ATF6, IRE1α, and PERK) was measured by western blotting in a panel of cancer cell lines expressing WT-KIT or MT-KIT. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | B Confocal microscopy was performed to evaluate the nuclear localization of ATF6 in various cancer cell lines selected from the cell line panel used in A. C Cell viability was measured in GIST cells treated with various doses (0.1–5 µM) of an ER-stress inducer, thapsigargin (TG) for 24 h. D GIST cells were treated with 5 µM TG (strong ER-stressor) across various timepoints, and the expression of the three arms of the UPR pathway, a cell-death marker (CHOP), and KIT was measured by western blotting. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | E GIST cells were treated with 0.1 µM TG (mild ER-stressor) across various timepoints, and the expression of the markers measured in D and chaperones (HSP70, HSP90, BIP, and GRP94) was measured by western blotting. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | F Expression of ATF6 and chaperones was measured by western blotting after treatment with 30 µM PF429242 (PF), which blocks ATF6 cleavage. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | G Cell viability of GIST cells treated with 0.1 µM TG and PF was measured after 24 and 48 h. H Immunoprecipitation of GIST cell lysates was performed with a control IgG or KIT antibody, and western blotting was performed against chaperones. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Error bars in C and G represent the SD of the mean of three independent experiments. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | One-way ANOVA with a post-hoc test was performed to compare multiple means (*p < 0.05, **p < 0.01, ***p < 0.001). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To investigate ATF6 involvement in the intrinsic tolerance of GISTs to ER stress, the GIST cell viability was measured 24 h after treatment with an ER stress inducer thapsigargin (TG). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | GIST cells were treated with various concentrations of TG commonly used in previous studies . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | TG treatment decreased GIST cell viability in a dose-dependent manner (0.1–5 µM) (Fig. 4C). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Based on the results, mild (0.1 µM TG) and strong (5 µM TG) ER stress-inducing conditions were selected. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Because of drastic cell death after 24 h of treatment with 5 µM TG, the activation status of ATF6, IRE1α, and PERK was measured for up to 8 h. The expression of CHOP (a cell death-related marker) and MT-KIT was also measured. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Western blot analysis showed that strong ER stress rapidly and drastically reduced ATF6, cleaved-ATF6 (cATF6), and MT-KIT levels over time, whereas phospho-IRE1α, phospho-PERK, and CHOP levels drastically increased after 1 h of treatment with TG and continuously increased for 8 h (Fig. 4D). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | In the case of mild ER stress, ER stress-adaptive chaperones (BIP, GRP94, HSP70, and HSP90) were analyzed for up to 24 h. ATF6, cATF6, and MT-KIT levels showed a moderate decrease until 8 h of treatment with TG but were fully restored after 24 h of TG treatment. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | On the other hand, phospho-IRE1α, phospho-PERK, and CHOP levels increased until 8 h of TG treatment, but were reduced to basal levels after 24 h. HSP90, BIP, and GRP94 levels gradually increased up to 24 h of TG treatment, while CHOP levels showed a gradual decrease after it peaked at 4 h of post-treatment (Fig. 4E). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To validate the direct involvement of ATF6 pathway in mild ER stress adaptation of GISTs, an ATF6 inhibitor, PF429242 (PF), was used to block ATF6 cleavage. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | PF was used at a concentration of 30 µM commonly used in previous in vitro and in vivo studies . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Western blot analysis showed that PF effectively inhibited ATF6 cleavage, and was accompanied by a drastic decrease in HSP90, BIP, and GRP94 levels (Fig. 4F). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Under PF-mediated ATF6 inhibition, even mild TG resulted in a dramatic cell death (Fig. 4G). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The upregulation of HSP90, BIP, and GRP94 was significantly delayed in GIST cells treated with both PF and mild TG. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The upregulation of CHOP remained even after 24 h of TG and PF treatment (Supplementary Fig. S12). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Next, the relationship between sustained ATF6 activation and folding and overexpression of MT-KIT was investigated to analyze the interaction between the MT-KIT and chaperones. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Immunoprecipitation analysis showed that MT-KIT specifically bound to HSP90 (Fig. 4H). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | These results suggest that ATF6 plays a pro-survival role against ER stress-mediated cell death, which also benefits MT-KIT folding. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To verify the significance of ATF6 as a therapeutic target in GISTs, the antitumor effects of PF, Ceapin-A7, and melatonin, which are reported ATF6 inhibitors, were investigated. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The efficacy of these inhibitors in combination with ER stress-inducing drugs, such as bortezomib and 17AAG, were further evaluated. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To mimic a constant ER stress condition in vivo, analysis was performed with or without TG, and imatinib was used as a control drug. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Cell viability analysis showed that ATF6 inhibitors alone efficiently suppressed GIST cell growth, irrespective of imatinib resistance, while the antitumor effect was synergistically enhanced when the ATF6 inhibitors are combined with ER stress-inducing drugs. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The synergistic antitumor effect was also observed with imatinib (Fig. 5A, B, and Supplementary Fig. S13). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The synergistic effects between ATF6 inhibition and other drugs (bortezomib, 17AAG, and imatinib) were assessed using the highest single agent (HSA) score analysis . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The results of the calculations revealed significant synergistic effects (HSA score >10) when ATF6 inhibition with PF429242 was combined with any of the drugs (Supplementary Fig. S14).Fig. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | 5Synergic anti-cancer effect of ER stress inducer and ATF6 inhibitor combination treatment on GIST growth, and the prognostic significance of ATF6 nuclear expression in patients with GIST.A, B Cell viability after 72 h of treatment with PF429242 alone (PF, 30 µM and 50 µM) and PF with ER stress-inducing drugs (0.5 µM 17AAG and 1 nM bortezomib) was analyzed in imatinib-sensitive GIST430 and GIST882 cells, and imatinib-resistant GIST48 and GIST430-V654A cells. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Imatinib (IM, 0.1 uM) was used as a control drug and the combined effect with PF was evaluated. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | C The expression of KIT and cATF6 was measured by western blotting after treatment of PF (30 µM). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | D The anti-tumor effect was measured in a GIST430 xenograft mouse model and GIST430-V654A model. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Relative tumor volume was measured at indicated days in vehicle, IM (50 mg/kg), PF (30 mg/kg), bortezomib (Bor, 1 mg/kg), and PF with bortezomib treatment groups. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Each group consisted of 5 mice. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | E, F Immunohistochemistry (IHC) analysis of KIT, Ki67, and cleaved caspase-3 was performed using tumor tissues obtained from xenograft mouse models. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | G Nuclear expression of ATF6 was evaluated by IHC analysis in 42 GIST tissues. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Patients were divided into nuclear ATF6 expression negative and positive groups. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | H Relapse-free and overall survival curves were plotted by Kaplan–Meier analysis and assessed by log-rank test, according to nuclear ATF6 expression. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Error bars represent the SD of the mean of three independent experiments. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | One-way ANOVA with a post-hoc test was performed to compare multiple means (*p < 0.05, **p < 0.01, ***p < 0.001). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | A, B Cell viability after 72 h of treatment with PF429242 alone (PF, 30 µM and 50 µM) and PF with ER stress-inducing drugs (0.5 µM 17AAG and 1 nM bortezomib) was analyzed in imatinib-sensitive GIST430 and GIST882 cells, and imatinib-resistant GIST48 and GIST430-V654A cells. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Imatinib (IM, 0.1 uM) was used as a control drug and the combined effect with PF was evaluated. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | C The expression of KIT and cATF6 was measured by western blotting after treatment of PF (30 µM). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | D The anti-tumor effect was measured in a GIST430 xenograft mouse model and GIST430-V654A model. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Relative tumor volume was measured at indicated days in vehicle, IM (50 mg/kg), PF (30 mg/kg), bortezomib (Bor, 1 mg/kg), and PF with bortezomib treatment groups. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Each group consisted of 5 mice. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | E, F Immunohistochemistry (IHC) analysis of KIT, Ki67, and cleaved caspase-3 was performed using tumor tissues obtained from xenograft mouse models. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | G Nuclear expression of ATF6 was evaluated by IHC analysis in 42 GIST tissues. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Patients were divided into nuclear ATF6 expression negative and positive groups. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | H Relapse-free and overall survival curves were plotted by Kaplan–Meier analysis and assessed by log-rank test, according to nuclear ATF6 expression. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Error bars represent the SD of the mean of three independent experiments. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | One-way ANOVA with a post-hoc test was performed to compare multiple means (*p < 0.05, **p < 0.01, ***p < 0.001). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Treatment with each ATF6 inhibitor potently downregulated cATF6 and KIT levels (Fig. 5C and Supplementary Fig. S15). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | In the presence of TG, the anti-tumor effect of each ATF6 inhibitor, with or without ER stress-inducing drugs, was slightly enhanced (Supplementary Fig. S16). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | In addition, the antitumor effect of PF was evaluated using a panel of cell lines, including a mutant KIT-expressing leukemia cell line (Kasumi), wild type KIT-expressing cell lines (Colo320DM and H128), and KIT-negative cell lines (HeLa, Capan-1, and MDA-MB-231). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The antitumor effect of PF was found to be minimal, regardless of the presence of TG (Supplementary Fig. S17). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To verify this, GIST xenografts were generated using GIST430 and GIST430-V654A cells. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The antitumor effect of PF with or without bortezomib was then assessed, and imatinib was used as a control drug. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | As expected, the GIST430 xenograft model was sensitive to imatinib, while the GIST430-V654A model was resistant to imatinib. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Treatment with PF (30 mg kg) potently inhibited tumor growth irrespective of imatinib sensitivity. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | In contrast, treatment with bortezomib alone (1 mg/kg) resulted in a slight suppression of tumor growth, irrespective of imatinib sensitivity. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | These findings indicate that ER stress induction alone is not sufficient to effectively suppress GIST growth. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | When combined with bortezomib, the antitumor efficacy was synergistically enhanced, especially in the imatinib-resistant GIST430-V654A model (Fig. 5D). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | IHC was performed using mouse tissues to measure the protein levels of KIT, Ki67, and cleaved caspase-3. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | KIT and Ki67 levels gradually decreased in the following order: bortezomib, imatinib, PF, and PF with bortezomib, whereas cleaved caspase-3 showed the opposite (Fig. 5E, F, and Supplementary Fig. S18). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | To demonstrate the clinical significance of ATF6 in GISTs, ATF6 expression in 42 patient tissues was analyzed. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | IHC analysis revealed that 33% of the patients (14/42, H-score ≤10) showed negative nuclear ATF6 expression, while 67% of the patients (28/42, H-score >10) showed positive nuclear ATF6 expression (Fig. 5G, Supplementary Table S1). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Survival analysis indicated that patients with nuclear ATF6 expression had significantly shorter relapse-free survival (P = 0.033) and a tendency for shorter overall survival (P = 0.339) (Fig. 5H). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Moreover, nuclear ATF6 expression showed significant correlation with recurrence or metastasis (P = 0.026; Supplementary Table S1). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | No significant association between KIT mutation and ATF6 expression was observed (data not shown). |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The KIT mutation status and details of imatinib treatment for the 42 patients are described in Supplementary Table S2. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Gain-of-function mutations in KIT are found even in the smallest GISTs and are therefore considered as an early oncogenic milestone of GIST tumorigenesis . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Xiang et al. were the first to report that pathogenic KIT signaling occurs from the Golgi. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | They demonstrated that hKIT becomes trapped in the endoplasmic reticulum (ER) in murine cells but localizes to the Golgi when expressed in human A375 cells. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | This difference was attributed to species-specific posttranslational modifications . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Subsequently, our group and others reported that both imatinib-sensitive and imatinib-resistant MT-KIT accumulate on the Golgi during the early secretory pathway. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Furthermore, they found that MT-KIT becomes fully auto-phosphorylated exclusively on the Golgi and only in a complex-glycosylated form. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Additionally, Obata et al. reported that the inhibitor of protein trafficking from the ER to the Golgi, 2-methylcoprophilinamide, suppresses KIT autophosphorylation, underscoring the importance of Golgi localization of MT-KIT in GIST tumorigenesis . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | The previous findings mentioned above raise more questions, such as how MT-KIT fully folds into a functional protein without interruption of ERQC and how it activates downstream signaling in the Golgi complex. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Several studies on GISTs have assumed that MT-KIT localized in the PM delivers downstream signaling . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | However, mutations in membranous proteins often result in unexpected changes in their localization and function. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | For instance, a cystic fibrosis transmembrane conductance regulator with a phenylalanine deletion at position 508 is targeted by PMQC and is therefore undetectable on the cell surface . |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Similarly, our findings showed that only a small portion of MT-KIT reached the PM and was rapidly degraded through PMQC. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | Moreover, inhibition of trans-Golgi-to-PM trafficking did not affect MT-KIT downstream signaling in GIST. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | These results suggest that membranous MT-KIT shows a loss-of-function phenotype rather than a gain-of-function phenotype, and therefore, membranous MT-KIT is hardly involved in GIST tumorigenesis. |
PMC10589262 | Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT | These findings may explain why some therapeutic trials using KIT antibody targeting membranous KIT failed to show antitumor effects in GIST xenograft models . |
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