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PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Moreover, the usefulness of F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and findings about the glycolytic system as a biomarker in GIST are presented.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
For details, please refer to sections from Glucose transporter (GLUT) to Biomarkers.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Fig 1 A schematic illustration of the relationship between gastrointestinal stromal tumor (GIST) and glycolysis and oxidative phosphorylation (OXPHS).
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Particularly, we focused on the relationship bwtween GIST and imatinib, a representative drug for treating GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Moreover, the usefulness of F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and findings about the glycolytic system as a biomarker in GIST are presented.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
For details, please refer to sections from Glucose transporter (GLUT) to Biomarkers.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
EVs: extracellular vesicles; GLUT: glucose transporter; HK1: hexokinase 1; PKM2: pyruvate kinase M2; LDH: lactate dehydrogenase; MCT: monocarboxylate transporter; MTV: metabolic tumor volume; PFS: progression-free survival: RFS: recurrence-free survival; SUVbsa: standardized uptake value corrected for body surface area; SUVbw: standardized uptake value corrected for body weight; SUVlbm: standardized uptake value corrected for lean body mass; TLG: total lesion glycolysis Considering substantial evidence regarding lactate and altered cellular metabolism in various cancers, targeting these aspects is now a major focus for pharmaceutical drug development .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
While research has highlighted the effectiveness of glycolysis pathway inhibitors in various cancer types and their anti-GIST potential is being explored, several aspects remain unclear .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GLUT inhibitors have started being increasingly recognized for their potential to target glucose dependency in cancer and other diseases, thereby opening new avenues for future drug development .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Our research indicated that WZB117 induced apoptosis in imatinib-resistant GIST cells .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
To the best of our knowledge, no other studies have reported on the association between GLUT inhibitors and GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Gossypol, a recognized LDHA inhibitor, and 3-bromopyruvate (3-BP), an inhibitor of HK2, have demonstrated efficacy against specific imatinib-resistant GIST cell lines.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, the mechanism underlying these cell growth suppressions is yet to be elucidated .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
2-deoxyglucose (2DG), an HK inhibitor, has been identified as a potential agent for treating tumors .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
While an in vitro study has demonstrated that 2DG possesses significant disease-specific effects, its primary action in GIST is not the disruption of energy production through glycolysis inhibition.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
2DG primarily functions by inhibiting KIT through suppression of KIT glycosylation .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Targeting MCT has emerged as a potential therapeutic strategy in cancer.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Pharmacological and genetic suppression of MCT1 or MCT4 lead to reduced tumor cell proliferation in vitro and in vivo, making them promising therapeutic targets .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
While the efficacy of MCT inhibitors has been indicated in several types of tumors , there is currently no evidence supporting their anti-GIST efficacy.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
As shown in Fig. 2, it is noteworthy that very few reports have demonstrated the efficacy of drugs targeting the glycolytic system in GIST.Fig.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
2A schematic representation of aerobic glycolysis and its inhibitors in gastrointestinal stromal tumor (GIST) cells.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The three drugs (WZB117, 3-BP, and Gossypol) inhibit glucose transporter (GLUT), hexokinase 2 (HK2), and lactate dehydrogenase (LDH), respectively.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Only these three glycolytic inhibitors are potentially effective against GISTs.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Note: 2-Deoxyglucose (2DG) serves as an HK inhibitor; however, its principal action within GIST does not primarily involve the curtailment of energy generation through inhibition of glycolysis.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Instead, it mainly operates through repression of KIT by suppressing KIT glycosylation.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Fig 2 A schematic representation of aerobic glycolysis and its inhibitors in gastrointestinal stromal tumor (GIST) cells.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The three drugs (WZB117, 3-BP, and Gossypol) inhibit glucose transporter (GLUT), hexokinase 2 (HK2), and lactate dehydrogenase (LDH), respectively.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Only these three glycolytic inhibitors are potentially effective against GISTs.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Note: 2-Deoxyglucose (2DG) serves as an HK inhibitor; however, its principal action within GIST does not primarily involve the curtailment of energy generation through inhibition of glycolysis.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Instead, it mainly operates through repression of KIT by suppressing KIT glycosylation.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
2PG: 2-phosphoglycerate; 3-BP: 3-bromopyruvate; ENO: enolase; Fructose 6-P: fructose-6-phosphate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; Glucose 6-P: glucose-6-phosphate; LDH: lactate dehydrogenase; MCT: monocarboxylate transporter; PEP: phosphoenolpyruvate; PFK: phosphofructokinase; PK: pyruvate kinase As discussed in this review, the critical association between GIST and glycolysis is yet to be fully elucidated.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Given the rarity of GIST and the limited treatment options currently available, there is a compelling need for further exploration of the association between GIST and glycolysis.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Such investigations can potentially unveil novel anti-GIST therapeutic strategies in the future.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Furthermore, the mechanism of imatinib resistance should be clarified from the perspective of the glycolytic system and strategies to overcome imatinib resistance should be developed.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Glycolysis inhibition represents a promising target for therapeutic development.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Despite several key molecules in the glycolysis pathway, only three glycolytic inhibitors exhibit potential anti-GIST efficacy.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Furthermore, differences exist among effective inhibitors depending on the metabolic phenotype of the cell lines.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Further studies are required to substantiate these findings and establish the effectiveness of glycolysis inhibitors as potential anti-GIST therapeutic targets.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
This review discusses the involvement of glycolysis-related molecules in the pathogenesis of GIST and their potential as therapeutic targets.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
It also explores prospects for GIST research within glycolysis.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Targeting glycolysis as a therapeutic approach shows significant promise as a novel strategy for GIST treatment.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The insights gained from the reviewed reports hold the potential to lead to significant advancements in the field of GIST treatment.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Takafumi Shima: Data curation, Investigation, Writing – original draft.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Kohei Taniguchi: Writing – review & editing.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Yosuke Inomata: Writing – review & editing.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Jun Arima: Writing – review & editing.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Sang-Woong Lee: Writing – review & editing.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The author is not an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for Neoplasia and was not involved in the editorial review or the decision to publish this article.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: none
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Targeting ferroptosis as a novel approach to tumor treatment has gained attention.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe levels, and decreased glutathione levels in GIST.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
This effect could be partially inhibited by Ferrostatin-1.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.Gastrointestinal stromal tumor (GIST) is the most common tumor of mesenchymal origin in the gastrointestinal tract, with an annual incidence of 1/100,000–2/100,000 .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
C-kit mutations are detected in 75%-80% of patients, whereas platelet-derived growth factor receptor alpha (PDGFRA) gene mutations only account for 5%-10% .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Early diagnosis of GIST is often difficult.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Surgical resection remains the most effective treatment, but recurrence and metastasis often occur postoperatively.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
In addition, GIST is insensitive to radiotherapy and chemotherapy, making the prognosis poor.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Although the emergence of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of GIST patients, including Imatinib (IM) as the first-line treatment for recurrent, metastatic, and unresectable GIST , about 50% of GIST patients may develop acquired drug resistance within 2 years of treatment .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Although TKIs have been developed to the fourth generation, acquired drug resistance remains a problem.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
As a result, the overall treatment outcome of GIST remains unsatisfactory, and the latest clinical and basic research has focused on the new therapeutic targets .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Ferroptosis, a regulated cell death caused by fatal lipid peroxidation was proposed by Dixon in 2012 .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Subsequent studies identified lipid peroxidation as a key factor triggering membrane oxidative damage during ferroptosis .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Lipid peroxides are the result of oxidative damage to polyunsaturated fatty acids (PUFAs) caused by reactive oxygen species (ROS).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
This oxidative damage can disrupt the lipid bilayer and impact membrane function, ultimately leading to ferroptosis .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Inside the cell, the clearance of lipid peroxides primarily relies on the activity of the antioxidant enzyme glutathione peroxidase 4 (GPX4).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
GPX4 utilizes glutathione (GSH) as a substrate to convert lipid peroxides into normal phospholipid molecules.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The synthesis of GSH is contingent on the availability of intracellular cysteine, which can be generated from cystine imported from the extracellular space via the cysteine-glutamate antiporter (Systemxc-, composed of recombinant solute carrier family 7, member 11, SLC7A11, and recombinant solute carrier family 3, member 2, SLC3A2) .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Because GPX4 is the sole cellular enzyme capable of reducing lipid peroxides to lipids, it plays a critical role in ferroptosis and serves as the target for various ferroptosis inducers .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
A variety of tumors have been reported to be associated with ferroptosis, and targeting ferroptosis against tumor development and progression has become a promising approach in tumor therapy .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Several drugs have been identified to act through ferroptosis induction in different tumors, mainly including Systemxc- inhibitors (Erastin, sulfasalazine, sorafenib), glutathione depletion factor (FIN56), and GPX4 inhibitors (RSL3).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Notably, sulfasalazine and sorafenib have received approval from the US Food and Drug Administration (FDA) for clinical use [12–16].
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
However, the existence of ferroptosis in GIST and its mechanism remain unclear.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The ubiquitin-proteasome pathway regulates target protein degradation, involving ubiquitin-activating enzyme 1 (E1), ubiquitin-conjugating enzyme 2 (E2) and ubiquitin ligase enzyme 3 (E3).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Dysfunctional ubiquitin E3 ligase expression determines ubiquitination specificity and rate-limiting steps, playing a crucial role in tumor development .
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
STUB1, also known as the C terminus of HSP 70 interacting protein (CHIP), contains a tetratricopeptide repeat and a U-box, which is a ubiquitin E3 ligase targeting various oncogene-encoded proteins (such as p53, c-Myc, PTEN, AR-V7, and EGFR) [19–22].
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST and identify STUB1 as a novel ubiquitin E3 ligase targeting GPX4.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Moreover, we demonstrate the synergistic effect of IM combined with RSL3 in treating GIST, suggesting that inhibiting GPX4 to induce ferroptosis could enhance GIST therapy.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
GIST-T1 cell line was purchased from Cosmo Bio Co. Ltd. (Tokyo, Japan) and GIST-882 cell line was provided by Dr. Fletcher of Harvard Medical School.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Both cell lines were verified by short tandem repeat (STR) profiling and tested negative for mycoplasma contamination.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Human GIST cell lines (GIST-T1 and GIST-882) were cultured in Iscove’s Modified Dulbecco Medium (IMDM, Corning, #10–016-CV, USA) and RPMI 1640 medium (Gibco, #11875119, USA) supplemented with 10% fetal bovine serum (FBS, Gibco, #10099141C, USA) and 1% penicillin-streptomycin (Gibco, #15140122, USA).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Cells were passaged at 70%–80% confluence by dissociation from plates using 0.25% Trypsin-EDTA (Gibco, #25200056, USA).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
All cells were incubated in a 37°C incubator (Forma, USA) containing 5% CO2.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The cells were seeded in a 96-well plate with 2 × 10 cells and 100 µl medium per well.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
After culturing for some time, the medium was replaced with 100 µl medium with 10 µl cell counting kit-8 (#40203ES76, CCK-8, Yeasen, China).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
After 2 hours, the 96-well plate was oscillated for 2 min.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The absorbance value was detected with a microplate reader (Thermo Fisher, USA) at 450 nm.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Three replicate wells were run in each experiment, and each experiment was repeated three times.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The cell viability results were normalized to the number of cells in the control group.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Drug inhibition assay was performed by seeding and incubating 5 × 10 GIST-T1 or GIST-882 cells at 37 °C overnight.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Cells were treated with RSL3 and IM at various doses, and the half-maximal inhibitory concentration assay (IC50) was calculated using nonlinear regression analysis in GraphPad Prism 8.0.2.
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The synergistic effect of the combination treatment was measured using CompuSyn software (Paramus, NJ, USA).
PMC10728200
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
The combination index (CI) >1, =1, and <1 indicate antagonistic, additive, or synergic effects, respectively.