PMCID string | Title string | Sentences string |
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PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This process ultimately supports tumor cell survival and proliferation while inhibiting apoptosis Tumor Metabolism and Apoptosis Inhibition Mechanisms Driven by SDH Deficiency (Created by BioRender). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This figure illustrates the key molecular mechanisms underlying GIST associated with SDH deficiency, observed in approximately 15% of GIST cases. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The accumulation of succinate and fumarate affects the PHD and HIF signaling pathways, subsequently activating the MAPK pathway. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This process ultimately supports tumor cell survival and proliferation while inhibiting apoptosis In addition, GIST exhibits high levels of ETV1 expression, a transcription factor downstream of the MEK-MAPK pathway. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | ETV1 is essential for ICC development and its transformation into GIST cells, driving abnormal proliferation and inhibiting apoptosis . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The activation of KIT synergizes with ETV1, further promoting aberrant cell proliferation and apoptosis suppression . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Other genetic alterations, such as SDH gene silencing and mutations in RAS, BRAF, NF1, and FGFR1, have also been identified in a minority of GIST cases . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | These genetic changes present potential targets for individualized therapy. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | With the advancement of targeted therapy, systemic treatment of GIST has significantly progressed, primarily focusing on tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | However, GIST exhibits considerable molecular heterogeneity. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Approximately 5–10% of patients have succinate dehydrogenase (SDH)-deficient GISTs , which are more frequently seen in younger individuals and often associated with hereditary syndromes. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | SDH deficiency leads to succinate accumulation and activation of oncogenic signaling pathways . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This subtype responds poorly to conventional TKIs and displays distinct molecular features such as high expression of neural markers, FGFR signaling activation, and epithelial-mesenchymal transition (EMT), indicating the need for alternative therapeutic approaches . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | In PDGFRA-mutant GISTs, the D842V mutation (exon 18), which accounts for approximately 5% of cases, confers primary resistance to imatinib and sunitinib. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The novel TKI avapritinib has demonstrated promising efficacy in this mutation subtype and represents a new direction for precision therapy . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Moreover, the efficacy of immune checkpoint inhibitors (ICIs) in GIST remains uncertain. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Studies have shown that SDH-deficient GISTs possess an immune-cold microenvironment, which may influence their response to ICIs . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | In addition, immune-related adverse events (irAEs), such as hearing loss, have been reported during ICI treatment and warrant attention . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The neutrophil-to-eosinophil ratio (NER) has recently been proposed as a potential prognostic biomarker. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Although its role in GIST is not well-established, it may offer insights for future personalized treatment strategies . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | KIT and PDGFRA have been identified in treating GIST as type III receptor tyrosine kinases, leading to TKIs such as imatinib (IM). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | As a targeted therapy, IM has become one of the standard treatments for GIST. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | It inhibits tumor growth by suppressing the tyrosine kinase activity of KIT and PDGFRA . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Over the past two decades, IM has significantly improved the median survival of patients, extending it from 18 months to over 5 years . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Although IM remains the first-line therapy for GIST, disease progression typically occurs after a median duration of 20–24 months . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The most studied mechanism of IM resistance involves secondary mutations in KIT or PDGFRA and the activation of alternative pathways such as MEK-MAPK and PI3K-AKT. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This phenomenon, known as secondary resistance, limits the effectiveness of IM . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | These mutations primarily occur in the ATP-binding domain (exon 13 or 14 of KIT; exon 14 of PDGFRA) or the activation loop (exon 17 of KIT; exon 18 of PDGFRA) [27–30]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Sunitinib and regorafenib are currently used as standard second and third-line therapies for IM-resistant GIST . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | However, treating secondary resistance remains challenging, as the molecular mechanisms underlying resistance to these drugs are not fully understood. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Studies suggest that IM can induce autophagy, possibly contributing to developing secondary resistance . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Additionally, IM has been shown to induce ferroptosis and apoptosis [35–40], highlighting programmed cell death (PCD) as a promising therapeutic target for GIST. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Table 1 summarizes the major drugs currently used for GIST treatment, their targets and mechanisms of action. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Table 1Key drugs, their targets, and signaling pathways in the treatment of GISTDrug NameTargetSignaling pathwayRole in GIST treatmentImatinibc-Kit, PDGFRInhibits the activation of c-Kit and PDGFR, blocking tumor cell proliferation and survival signaling pathwaysEffective in the treatment of GIST, especially in patients with c-Kit mutations, inhibiting tumor cell proliferation and survivalSorafenibVEGFR, c-Kit, PDGFRInhibits VEGFR, c-Kit, and other receptors, suppressing tumor angiogenesis and cell proliferation pathwaysIn GIST, it inhibits tumor angiogenesis and enhances apoptosisLapatinibEGFR, HER2Inhibits the activation of EGFR and HER2, disrupting tumor cell proliferation, survival, and metastasis signaling pathwaysExhibits antiproliferative effects on HER2-positive GIST cells, slowing tumor progressionDocetaxelMicrotubulesInhibits microtubule depolymerization, interfering with cell division and mitosis, promoting apoptosisEnhances apoptosis of GIST cells and inhibits tumor growth in treatmentDoxorubicinDNA, Topoisomerase IIBinds to DNA and inhibits topoisomerase II, disrupting DNA replication and repair, inducing cell deathInhibits GIST cell proliferation and induces apoptosis through DNA damageBevacizumabVEGFInhibits VEGF, suppressing tumor angiogenesis and slowing tumor growthReduces blood supply to GIST tumors, inhibiting proliferation and metastasisCyclophosphamideDNA, Antigen PresentationBinds to DNA, inhibits DNA repair, triggers immune responses, and enhances cell deathIn adjuvant therapy for GIST, enhances immune system recognition and clearance of tumorsVemurafenibBRAFInhibits BRAF mutations, suppressing the MAPK pathway, reducing cell proliferation and inducing apoptosisPrimarily used for BRAF-mutant tumors, modulating cell cycle and apoptosis processes Key drugs, their targets, and signaling pathways in the treatment of GIST PCD encompasses various forms, including classical apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, each playing distinct roles in tumor malignancy and therapeutic responses [41–43]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | In GIST, apoptosis, autophagy, and ferroptosis are the primary forms of cell death. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Table 2 summarizes the key regulatory factors involved in these pathways and their functional impacts on GIST cells. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The apoptotic pathway is regulated by p53 and the Bcl-2 family, while autophagy involves Beclin-1, LC3, and the mTOR pathway. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Ferroptosis is controlled by glutathione peroxidase 4 (GPX4), ferroportin, and the Fenton reaction. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Studies have shown that suppression of apoptosis correlates with poor prognosis in GIST patients, whereas the role of autophagy can vary under different conditions [33, 44–46].Table 2Molecular regulators of cell death mechanisms in GISTCell Death TypeRegulatorMechanism of ActionRole in GISTApoptosisp53p53 upregulates pro-apoptotic genes such as Bax, promoting mitochondrial release of cytochrome C, and activating caspase family membersp53 mutations or inactivation inhibit apoptosis, promoting tumor cell survivalBcl-2 FamilyBcl-2 proteins regulate mitochondrial membrane permeability, inhibiting pro-apoptotic signals, and maintaining cell survivalIn GIST cells, Bcl-2 expression is upregulated, inhibiting apoptosisCaspasesThe caspase family is key in executing apoptosis by cleaving various intracellular substrates, leading to cell deathCaspase-3 and other enzymes are inhibited in GIST, reducing apoptosis occurrenceAutophagyBeclin-1Beclin-1 is a crucial regulator in the early stages of autophagy, promoting the formation of autophagosomes and initiating autophagyBeclin-1 is expressed at low levels in GIST, leading to suppressed autophagyLC3LC3 proteins play a pivotal role in autophagosome formation by binding to autophagosomes and facilitating the autophagic processHigh expression of LC3-II indicates activation of autophagy in GIST cellsmTORmTOR suppresses the expression of autophagy-related genes, regulating the initiation and progression of autophagyThe mTOR pathway is hyperactivated in GIST cells, inhibiting the autophagy processFerroptosisGPX4GPX4 removes intracellular lipid peroxides, inhibiting ferroptosisIn GIST, GPX4 expression may be suppressed, promoting ferroptosisFerroportinFerroportin is the main protein for cellular iron transport, controlling iron export and regulating intracellular iron levelsFerroportin expression is decreased in GIST, exacerbating iron accumulationFenton ReactionIron ions generate free radicals through the Fenton reaction, leading to oxidative stress and promoting ferroptosisExcess iron accumulation increases ROS in GIST cells, triggering ferroptosis Molecular regulators of cell death mechanisms in GIST Apoptosis has been reported to correlate with GIST malignancy, while autophagy generally exhibits an inverse relationship with apoptosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | During GIST progression, ferroptosis appears to function similarly to apoptosis, with ferroptosis-related proteins identified as potential targets and predictive markers for TKI therapy [35–37]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | As a novel therapeutic target, developing ferroptosis-specific drugs is promising for treating advanced GIST . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Apoptosis, one of the most extensively studied forms of PCD, is characterized by cellular shrinkage, an undulated yet intact plasma membrane, nuclear condensation, and fragmentation, indicative of its non-inflammatory nature. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Apoptotic cells exhibit characteristic morphological changes, including the formation of apoptosomes, which consist of apoptotic peptidase activating factor 1 (APAF1) and caspase-9 . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The apoptosis pathway is classified into intrinsic and extrinsic pathways and further divided into the mitochondrial pathway , death receptor pathway , and endoplasmic reticulum (ER) stress pathway . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The intrinsic (mitochondrial) and extrinsic pathways are the most extensively studied. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The extrinsic pathway is typically triggered by activating tumor necrosis factor (TNF) receptor family members . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The intrinsic pathway is initiated by increased mitochondrial outer membrane permeability (MOMP) and cytochrome c release, leading to apoptosome formation . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The Bcl-2 family plays a critical regulatory role in this pathway and is divided into three subfamilies: pro-apoptotic BH3-only proteins (e.g., Bim, Bid, Puma), anti-apoptotic Bcl-2 family members (e.g., Bcl-2, Mcl-1), and effector molecules (e.g., Bax, Bak) . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | In contrast, the extrinsic pathway is initiated by activating pro-apoptotic death receptors, which are cell membrane proteins, including Fas and TNFR. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Death receptors are activated by binding specific ligands, leading to the recruitment of adaptor proteins such as FADD via their death domains (DD) [58–60]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Evasion of apoptosis and the aberrant expression of survival proteins are among the most common alterations during malignant transformation. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | By avoiding apoptosis, malignant cells enhance their survival and develop drug resistance [61–63]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | As understanding of apoptotic mechanisms has advanced, a limited number of FDA-approved anticancer drugs have been developed to directly target apoptosis pathways. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Additionally, many FDA-approved anticancer drugs targeting cell survival and proliferation pathways exert their anti-tumor effects by modulating apoptotic signaling pathways . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This review examines the molecular functions of PCD pathways in GIST, focusing on their roles in the pathogenesis, malignancy, and responses to TKI therapies. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Additionally, we emphasize the significance of non-coding RNAs (ncRNAs) in these pathways, as growing evidence suggests that ncRNAs play critical roles across various pathways. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Investigating the interplay between these pathways and ncRNAs may offer new research directions and therapeutic strategies for GIST. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Apoptosis plays a key role in the pathogenesis and biology of GIST), particularly in changes in apoptotic signaling and drug resistance following TKI therapy, such as IM. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The most common driver mutations in GIST involve the KIT and PDGFRA genes, which activate multiple downstream signaling pathways that regulate cell survival and apoptosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Overexpression of the transcription factor ETV1 may facilitate the transformation of interstitial cells of Cajal into GIST cells while suppressing apoptosis, contributing to tumor progression. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Activating mutations in the c-KIT gene result in constitutive KIT tyrosine kinase activity, which provides continuous proliferative and survival signals—one of the central mechanisms in GIST pathogenesis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | While inhibition of apoptosis and dysregulation of the cell cycle are likely early molecular events in GIST, the precise mechanisms remain under investigation. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Driver mutations in KIT and PDGFRA activate multiple pathways that disrupt the expression and function of apoptotic regulators. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Constitutively active KIT signaling enables tumor cells to evade apoptosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Cyclin D1 is significantly overexpressed in KIT-independent GIST and is associated with antiproliferative and pro-apoptotic responses, indicating a role for cell cycle regulators in the transition from KIT dependence to resistance . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Alterations in E2F1, p53, p16, and p27KIP1 are more frequent in malignant GIST, further implicating apoptosis escape in tumor progression . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Bcl-2, a classic anti-apoptotic protein, is highly expressed in GIST and correlates with poor prognosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Cunningham et al. reported shorter survival in patients with high Bcl-2 expression, supporting its role in apoptosis evasion . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | APAF-1, a core component of the apoptosome, is negatively regulated by KIT expression, suppressing apoptosis in GIST . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | FAM96A, a tumor suppressor that enhances mitochondria-mediated apoptosis via interaction with APAF1, is significantly downregulated in GIST, suggesting a loss of pro-apoptotic function . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | FOXO transcription factors, particularly FOXO3a, promote apoptosis by upregulating BIM . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Apoptosis evasion supports GIST growth and survival and contributes to resistance. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Although IM has strong antiproliferative effects, it fails to induce sufficient apoptosis, pushing cells into a quiescent state, a potential source of resistance . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Upregulation of p27(Kip1) and loss of Cyclin A through the APC/CDH1-SKP2-p27(Kip1) axis facilitates apoptosis evasion and quiescence . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Apoptosis-related proteins are valuable biomarkers for predicting GIST behavior and prognosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Wang et al. demonstrated a correlation between telomerase activity, apoptotic intensity, and GIST malignancy, noting that apoptosis progressively declines in benign and potentially malignant GIST . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Risk stratification based on the Ki-67 index, tumor size, and location helps predict recurrence in IM-naive patients . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Nemoto et al. found that high-risk GIST cases exhibit elevated labeling indices (LIs) for Ki-67, ssDNA, Cyclin A, and CDK2, Survivin (BIRC5), an anti-apoptotic protein, inhibits the extrinsic pathway via interaction with XIAP . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Its expression is elevated in GIST and downregulated following KIT inhibition, implying a role in KIT-mediated survival signaling . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | FOXO proteins activate apoptosis through multiple mechanisms, including the induction of Bcl-2 pro-apoptotic members, expression of death ligands (e.g., FasL), and upregulation of CDK inhibitors (Fig. 2). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | FOXO1 influences GIST proliferation, apoptosis, and cell cycle through phosphorylation-dependent mechanisms .Fig. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | 2Fas-Mitochondria-Dependent Apoptosis Pathway (Created by BioRender). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This figure depicts how the extrinsic apoptosis pathway mediated by the death receptor Fas intersects with the mitochondrial pathway. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Mitochondrial release of cytochrome C forms apoptosomes, activating caspase family enzymes (such as Caspase-9, Caspase-3/6/7), which leads to apoptosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | However, survival inhibits this process Fas-Mitochondria-Dependent Apoptosis Pathway (Created by BioRender). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | This figure depicts how the extrinsic apoptosis pathway mediated by the death receptor Fas intersects with the mitochondrial pathway. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Mitochondrial release of cytochrome C forms apoptosomes, activating caspase family enzymes (such as Caspase-9, Caspase-3/6/7), which leads to apoptosis. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | However, survival inhibits this process Apoptosis is essential in determining the response to IM and in the development of drug resistance in GIST. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Although IM strongly inhibits proliferation, it often fails to trigger adequate apoptosis, resulting in low pathological complete response rates and high progression rates in metastatic disease . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Liu et al. reported that IM induces quiescence in some GIST cells, marked by p27(Kip1) upregulation, Cyclin A loss, and G0-G1 arrest . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The DREAM complex also plays a role in maintaining quiescence . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | IM alters apoptotic protein expression, revealing potential therapeutic targets. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Romeo et al. found that p53 and p16 expression independently affect PFS, highlighting the importance of apoptosis/cell cycle balance . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Osteopontin, via β-catenin signaling, upregulates Mcl-1, antagonizing IM-induced apoptosis . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | The FBXW7-Mcl-1 axis regulates IM sensitivity; FBXW7 suppresses Mcl-1 to enhance apoptosis and predict IM response . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Inhibiting BRD9 activates PUMA through the TUFT1/AKT/GSK-3β/p65 axis, enhancing IM-induced apoptosis . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Autophagy is a tightly regulated lysosome-dependent degradation pathway that ensures cellular homeostasis by eliminating damaged organelles, misfolded proteins, and invading pathogens . |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | It is classified into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | CMA selectively degrades soluble cytosolic proteins harboring a KFERQ-like motif, mediated by the LAMP-2A receptor and Hsp70 [83–85]. |
PMC12065685 | Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors | Macroautophagy, the most studied subtype, involves the formation of double-membraned autophagosomes, which engulf cytoplasmic cargo and fuse with lysosomes for degradation. |
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