PMCID string | Title string | Sentences string |
|---|---|---|
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We therefore estimated apoptosis in GIST48 after treatment with staurosporine (STS), used as positive control, and with VP or CA3. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In GIST48, neither VP nor CA3 induced apoptosis after 24 h of treatment, whereas STS strongly induced apoptosis after 4 h (Figure S3A). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In GIST882, we were unable to detect any activated caspase-3 in GIST882 cells, even in STS-treated cells (Figure S3B–E). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | To understand how VP and CA3 induce lipid peroxidation-mediated ferroptosis in GIST cell lines, ferrous iron and glutathione (GSH) concentrations were measured. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | VP significantly increased ferrous iron concentration in both GIST882 and GIST48 cells after 24 h. CA3 exhibited only a minor non-significant increase in ferrous iron in GIST48 cells, but not in GIST882 cells (Figure 6A). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | GSH is another key regulator of ferroptosis and its content could be reduced following ferroptosis induction. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We measured the GSH content after 24 h of treatment with VP or CA3 in both GIST882 and GIST48 (Figure 6B). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | VP treatment induced a significant depletion in the GSH content in GIST882 and a tendency towards a reduction in GIST48 cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Interestingly, while CA3 failed to significantly increase ferrous iron content, it significantly reduced the GSH content in both cell lines. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We conclude that VP acts on both iron and GSH metabolism, whereas CA3 mainly acts on antioxidant features of the cell through GSH metabolism. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The expression of a series of key ferroptotic genes (i.e., GPX4, NRF2, TFRC, SLC7A11 ACSL4, FTH1, and HMOX1), known to be affected following ferroptosis induction , was analyzed (Figure 7A). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The results showed that VP reduced the expression of TFRC mRNA in both GIST882 and GIST48 cells after 24 h of treatment (Figure 7A, upper panels). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The expression of other genes related to ferroptosis was not altered (Figure 7A, upper panels). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We could not detect any significant modifications in the mRNA expression of all ferroptosis-related tested genes after 24 h of CA3 treatment (Figure 7A, lower panels). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We extended the analysis by RNA sequencing (Figures S4 and S5). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The differentially expressed genes (DEGs) identified after 24 h of treatment with either VP or CA3 were compared with the FerrDb database composed of genes known to promote (drivers) and prevent (suppressors) ferroptosis (http://www.zhounan.org/ferrdb, accessed on 19 September 2022) . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Multidimensional scaling (MDS) plots showed that, except for VP-treated GIST882 cells, CA3-treated GIST882 and GIST48 cells and VP-treated GIST48 cells were not well separated from control cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The DEGs between untreated and VP-treated GIST882 cells were compared to the FerrDb database. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | It appeared that some ferroptosis suppressors were statistically downregulated (i.e., LAMP2, ACSL,3 and ENPP2) and two drivers were upregulated (i.e., CHAC1) (Figure S4C,D). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We also confirmed by qPCR that TFRC mRNA was downregulated in VP-treated GIST882 cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Except for the ENPP2 gene that was also downregulated in VP-treated GIST48 cells, the other ferroptosis-related DEG genes were not found in the other conditions, suggesting that VP and CA3 do not induce ferroptosis through major common changes in the expression of ferroptosis-related genes. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The mRNA expression of several genes downstream of YAP, CTGF, CYR61, and AMOTL2 was also analyzed by qPCR and RNA sequencing (Figure S6). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | While VP reduced, as expected for YAP inhibition, their expression in GIST882 and GIST48 cells, CA3 treatment, surprisingly, induced their up-regulation, rather than downregulation, in GIST882 cells, while no modification was observed in GIST48 cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We then questioned whether VP or CA3 modulate the expression of key proteins important for ferroptosis induction. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We assessed SLC7A11 and GPX4 protein expression. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Despite a reduction in the GSH content in both GIST882 and GIST48 by either VP or CA3 treatment, the SLC7A11 protein level was not affected in the two cell lines (Figure 7B,C). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Conversely, a significant decrease in the GPX4 protein level was observed in both VP- and CA3-treated GIST882 and GIST48 cells compared to untreated cells, although GPX4 mRNA was not affected (Figure 7D,E). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | These data provide a common link between VP and CA3, as well as a downregulation of the GPX4 protein, a key enzyme which prevents lipid peroxidation and ferroptosis. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | As the TFRC is described as a new cancer marker , the expression of the TFRC in human GIST tissues was assessed. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | IHC was performed on ovarian cancer tissue, used as a positive control to validate TFRC antibody immunoreactivity (-ir), and on five primary GIST tissues with different clinicopathological features (Table S1). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The TFRC-ir was observed in KIT- and YAP-positive regions of all GIST tissues tested (Figure 8). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | IHC was next performed on GIST tissue microarrays (TMAs) to increase the cohort and assess a potential correlation between the TFRC expression level and clinicopathological criteria, and/or YAP expression/activation. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Our cohort included a total of 96 GIST patients, with 9 being non-contributive because of poor tissue quality or loss during processing. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | GIST samples were stained for three markers, KIT, YAP, and TFRC (Figure 9A). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | All tissues displayed strong positive (++) or positive (+) KIT-ir, and TFRC-ir was also observed in all GIST specimens with a strong expression (+++) in 14% of the cohort, a moderate expression (++) in 45% of the cohort, and a weak expression (+) in 32% of the cohort (Figure 9B). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | YAP-ir was strongly positive (++) in 15% of GISTs, positive (+) in 66% of GISTs, and negative (−) in 10% of GISTs (Figure 9C). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Finally, 60% of GIST samples displayed cytoplasmic YAP-ir, suggesting that YAP is inactive, whereas 40% displayed an active YAP (4% and 36% of nuclear and mixed location YAP-ir, respectively) (Figure 9D). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Results of the correlation between TFRC-ir and histopathological GIST characteristics are summarized in Table 1. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Data on some histopathological criteria were missing for a few GIST samples. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | While no association was found in the mean size tumor between TFRC-ir, or between non-metastatic/metastatic GISTs, male/female, mutational status, or histological types, we found that the level of TFRC expression was associated with the mitotic index (p-value = 0.00061) and risk classification (p-value = 0.0228). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Analyses of these correlations revealed that TFRC+++ was associated with a high mitotic index (>5/5 mm²), while a lower expression of the TFRC (TFRC+) was associated with a lower mitotic index (≤5/5 mm²) (Figure 10A). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, TFRC+++ was correlated with high-risk cases of GISTs, while TFRC+ was associated with low-risk, very low risk, and no-risk GIST samples (Figure 10B). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We next investigated the link between TFRC and YAP expressions or activity in human GIST samples. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | YAP and TFRC expression (p-value < 0.0001), YAP activity, and TFRC expression were correlated (p-value = 0.00017) (Table 2). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Analyses of contingency tables showed that TFRC+++ was associated with YAP++ staining (Figure 10C). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | TFRC++ was correlated with YAP++/+ staining, whereas TFRC+ was associated with the absence of YAP expression in GIST samples (Figure 10C). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Active YAP (nuclear and mixed location) was associated with a TFRC+++/++, while inactive YAP (cytoplasmic location) was associated with a TFRC+. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | TFRC++ showed an association with both active and inactive YAP (Figure 10D). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | To summarize, our data reveal that a high level of TFRC is associated with an elevated mitotic index, high-risk GIST samples, and highly expressed and active YAP. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Conversely, a weak expression of the TFRC is associated with a lower mitotic index; a lower-risk GIST; and with a low, inactive, or absent YAP. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Recent studies support the potential of targeting ferroptosis in multiple cancers, such as triple-negative breast cancer , high-risk neuroblastoma , rhabdomyosarcoma , and others . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Cancer cells appear to be more sensitive to ferroptosis than normal cells, due to their “addiction to iron” required for proliferation on the one hand and their dependency on antioxidant systems on the other . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Ferroptosis can counteract apoptosis resistance and an induction of ferroptosis can sensitize cancer cells to their first-line therapy (radiotherapy and chemotherapy) . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | It is of note that non-epithelial (hematopoietic and lymphoid, bone tissue, ovary, soft tissue, etc.) |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | cancer cell lines have been shown to be more sensitive to ferroptosis than epithelial carcinomas . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Given that primary or secondary resistance to imatinib remains a major concern in GISTs, ferroptosis deserves further consideration in this type of cancer. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | A recent study from Ishida et al. demonstrated that the GPX4 inhibitor RSL3 induced ferroptotic cell death in imatinib-sensitive GIST-T1 cells and imatinib-resistant GIST-R8. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Lipid peroxidation was not reported in that study. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Their observations are in line with our data which demonstrate that RSL3 induced ferroptosis through important lipid peroxidation in the imatinib-sensitive and -resistant human GIST cells, GIST882 cells, and GIST48 cells, respectively. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, we showed that Lip, an antioxidant, reversed cytotoxicity and lipid peroxidation induced by RSL3. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | RSL3 treatment appeared to be efficient to inhibit tumor growth in BjeLR cell xenografts in mice , in prostate tumor models in vivo , in glioblastoma , and in GIST-T1 xenografts after imatinib therapy cessation . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Our in vitro data support the view that GPX4 inhibitors should be further evaluated in GIST xenograft models in vivo. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We previously reported that the YAP inhibitor VP induced massive cell death in both GIST882 and GIST48 cells, but the type of cell death involved remained unknown . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Here, we established that VP cytotoxicity is mediated by ferroptosis and confirmed that VP behaves like a canonical YAP inhibitor in GIST882 and GIST48 cells, since VP decreased the expression level of several known YAP transcriptional targets, as reported in other cell lines . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | CA3, recently reported as a YAP inhibitor , also demonstrated strong lipid peroxidation and marked a reduced viability reversed by ferroptosis inhibitors in both GIST882 and GIST48 cell lines. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Surprisingly, in view of the current literature, we observed a paradoxical increase, instead of a decrease, in the YAP transcriptional targets CTGF and CYR61, as well as in AMOTL2 mRNA expressions after CA3 treatment in GIST882, while no change was detected in GIST48. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | These results highlight that ferroptosis induced by CA3 appears to be uncoupled from the inhibition of the YAP transcriptional program in GIST882 and GIST48 cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Further studies will be required to unravel the CA3 mechanism of action in these cell lines. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | A positive regulation of YAP on ferroptosis has been reported in basal and luminal breast cancer, non-small cell lung cancer, clear-cell renal carcinoma and in mesothelioma cells . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Conversely, Gao et al. identified YAP as a negative ferroptosis regulator in hepatocellular carcinoma cells, in line with our present original data VP in GISTs. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Our data show that VP significantly increased ferrous iron levels in both GIST cell lines, which is in line with recent studies showing that inhibition of YAP sensitized cells to ferroptosis by increasing the labile iron pool . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | VP treatment also decreased TFRC mRNA expression, which is probably a defense mechanism to reduce iron uptake. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | However, the protective effect on cell viability elicited by the iron chelator DFO was not complete, suggesting that, although ferroptosis largely contributes to VP-mediated cytotoxicity, other cell death mechanisms might also be involved. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Apoptosis was ruled out in GIST48 cells, but other cell death mechanisms remain to be explored, as YAP has been shown to be associated with multiple cell death mechanisms . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Flow cytometry assays showed an increase in lipid peroxidation in GIST882 and GIST48 cells after both VP and CA3 treatments. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | CA3-mediated lipid peroxidation was completely inhibited by Lip and DFO, suggesting that ferroptosis is the major cell death mechanism induced by CA3 in GIST cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | However, those ferroptosis inhibitors were unable to completely inhibit lipid peroxidation in GIST882 and GIST48 cells after VP treatment. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The larger increase in labile iron pool in VP-treated cells compared to CA3-treated cells could be responsible for a larger ROS production through the Fenton reaction and an increased activity of iron-containing lipid peroxidases, which are crucial for lipid peroxidation induction . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We hypothesized that this would prevent DFO and Lip to fully counteract lipid peroxidation. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, we showed that the GSH content was reduced by CA3 or VP treatment in GIST882 and GIST48 cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Our in vitro data are in line with the results of Morishita et al. , who reported that a depletion in GSH was required for VP cytotoxicity in acute lymphoblastic leukemia patient-derived xenografts. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | A major antioxidant pathway that prevents ferroptosis is the SLC7A11/GSH/GPX4 axis . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In this study, no modification in SLC7A11 mRNA or protein expression was detected, despite a significant decrease in the GSH content. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | This suggests that VP and CA3 could modulate other genes involved in GSH biosynthesis. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Conversely, a significant depletion in GPX4 protein expression was observed in both GIST cell lines after treatment with VP or CA3, while GPX4 mRNA expression remained unaffected. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | These results are consistent with the degradation of the GPX4 protein level, independently of GPX4 mRNA changes, already observed in fibrosarcoma cells and BJeLR-engineered transformed fibroblast cells after treatment with another class II ferroptosis inducer, FIN-56 . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | It is noteworthy that FIN-56 is an analog of “caspase-3/7-independent lethals” compound CIL-56, otherwise known as CA3, the drug used in our study. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Although the link between CA3 (CIL-56) and ferroptosis has been controversial , our study provides evidence that CA3 (CIL-56) induces ferroptosis with a significant depletion in GPX4 protein levels in GIST cells. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The mechanisms underlying GPX4 protein reduction after treatment with VP or CA3 in GIST cell lines remain to be clarified. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | It has been reported in other models that GPX4 can be degraded via the ubiquitin–proteasome system, as shown in triple-negative breast cancer . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, some studies described mTORC1 as a key player in GPX4 protein synthesis and in the prevention of autophagy-mediated GPX4 degradation . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | A model which emerged from our results demonstrated a link between the inhibition of the YAP pathway and ferroptosis in GIST cells after VP treatment (Figure 11B). |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | The inhibition of YAP transcriptional program mediated by VP reduced GIST cell viability and increased lipid peroxidation, which were partially reversed by ferroptosis inhibitors. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, VP-treated GIST cells were characterized by an increase in free ferrous iron concentration and a depletion in the GSH content and GPX4 protein levels. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We also highlight a link between CA3 and ferroptosis induction through a significant increase in lipid peroxidation, a slight increase in the labile iron pool, and a major depletion in the GSH content and GPX4 protein levels, independently of the inhibition of the transcriptional program downstream of YAP. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | These results suggest that both VP and CA3 impair the balance between iron-mediated oxidative damage and antioxidant defenses through different molecular mechanisms in GIST882 and GIST48 cells, leading to further lipid peroxidation and ferroptosis as a cell death mechanism. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Iron is essential for biological processes including DNA synthesis and DNA repair, which are important for cell growth and proliferation. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Due to the high rate of proliferation in cancer cells, these cells appear to be “addicted to iron” . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Elevated iron in cancer cells allows tumor growth and progression. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In cancer cells, iron is mainly imported via the TFRC, and this transmembrane receptor has been found to be overexpressed in many types of cancers, such as brain, breast, colon, ovarian, and lung cancers, as well as in leukemia . |
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