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IFNγ synergies with cold atmospheric plasma in triggering colorectal cancer cell ferroptosis via the IFNγ/IFNR2/APC/TCF4/GPX4 axis.

ABSTRACT: Colorectal cancer accounts for the second most common cancer-related lethality. Intestinal stem cells are responsible for enteric homeostasis maintenance that, once being transformed, become colorectal cancer stem cells. Arresting cancer stemness represents an innovative strategy for colorectal cancer management. Using intestinal stem cell organoids as the primary model, we screened common inflammatory cytokines to identify key players targeting cancer stemness. We also explored the downstream signaling that drives the functionalities of the identified cytokine through both experimental investigations and computational predictions. As the results, we identified IFNγ as the key cytokine capable of arresting intestinal stem cells via the IFNγ/IFNGR2/APC/TCF4/GPX4 axis, proposed its role in killing colorectal cancer stem cells via triggering GPX4-dependent ferroptosis, and demonstrated its synergistic anti-cancer effect with cold atmospheric plasma in killing colorectal cancer cells that is worthy to be experimentally validated.

SUBMITTER: Lv X

PROVIDER: S-EPMC10522381 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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IFNγ synergies with cold atmospheric plasma in triggering colorectal cancer cell ferroptosis via the IFNγ/IFNR2/APC/TCF4/GPX4 axis.

Lv Xinyu X He Fu-le FL Dai Yilin Y Dai Xiaofeng X

Aging 20230904 17

Colorectal cancer accounts for the second most common cancer-related lethality. Intestinal stem cells are responsible for enteric homeostasis maintenance that, once being transformed, become colorectal cancer stem cells. Arresting cancer stemness represents an innovative strategy for colorectal cancer management. Using intestinal stem cell organoids as the primary model, we screened common inflammatory cytokines to identify key players targeting cancer stemness. We also explored the downstream s ...[more]

PMID: 37671945

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Project description:IntroductionFerroptosis, induced by iron overload and an imbalance in redox homeostasis, promotes the generation of reactive oxygen species (ROS), leading to iron-dependent lipid peroxides (LPO) and oxidative stress. Lipid peroxidation induced by reactive oxygen species is essential for the progression of spermatogenesis. However, its imbalance can lead to reproductive system damage and oligoasthenospermia, a critical cause of oligoasthenospermia. Isatin (ISA) is a naturally occurring compound that is widely distributed in lobsters, crustaceans, shellfish and various plants. It exhibits significant antioxidant and anti-aging properties, suggesting its potential as a therapeutic agent for the treatment of oligoasthenospermia. This study aimed to investigate the effects and mechanisms of ISA on oligoasthenospermia and to elucidate the underlying molecular pathways.MethodsAll mice were divided into normal group, model group and treatment group. Both model group and treatment group received a single intraperitoneal injection of 30 mg/kg BUS to create the model of oligoasthenospermia. After 2 weeks, the treatment group received different doses of 25, 50 and 100 mg/kg ISA by gavage for 28 days, and then mice were sacrificed and tested.ResultsThe results demonstrated that ISA effectively reversed busulfan-induced reproductive system damage in mice. This included the restoration of testicular histomorphology, improvement in sperm concentration and motility, regulation of serum sex hormone levels, and normalization of various oxidative indices in testicular tissue. Furthermore, ISA successfully reversed testicular ferroptosis by restraining the translocation of nuclear factor erythroid 2-related factor 2 (NRF2) into the nucleus and improved oligoasthenospermia through the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis.DiscussionISA was found to effectively ameliorate oligoasthenospermia in mice, presenting a potential therapeutic option for patients with this condition.

Project description:Gankyrin is found in high levels in triple-negative breast cancer (TNBC) and has been established to form a complex with the E3 ubiquitin ligase MDM2 and p53, resulting in the degradation of p53 in hepatocarcinoma cells. Therefore, this study sought to determine whether gankyrin could inhibit ferroptosis through this mechanism in TNBC cells. The expression of gankyrin was investigated in relation to the prognosis of TNBC using bioinformatics. Co-immunoprecipitation and GST pull-down assays were then conducted to determine the presence of a gankyrin and MDM2 complex. RT-qPCR and immunoblotting were used to examine molecules related to ferroptosis, such as gankyrin, p53, MDM2, SLC7A11, and GPX4. Additionally, cell death was evaluated using flow cytometry detection of 7-AAD and a lactate dehydrogenase release assay, as well as lipid peroxide C11-BODIPY. Results showed that the expression of gankyrin is significantly higher in TNBC tissues and cell lines, and is associated with a poor prognosis for patients. Subsequent studies revealed that inhibiting gankyrin activity triggered ferroptosis in TNBC cells. Additionally, silencing gankyrin caused an increase in the expression of the p53 protein, without altering its mRNA expression. Co-immunoprecipitation and GST pull-down experiments indicated that gankyrin and MDM2 form a complex. In mouse embryonic fibroblasts lacking both MDM2 and p53, this gankyrin/MDM2 complex was observed to ubiquitinate p53, thus raising the expression of molecules inhibited by ferroptosis, such as SLC7A11 and GPX4. Furthermore, silencing gankyrin in TNBC cells disrupted the formation of the gankyrin/MDM2 complex, hindered the degradation of p53, increased SLC7A11 expression, impeded cysteine uptake, and decreased GPX4 production. Our findings suggest that TNBC cells are able to prevent cell ferroptosis through the gankyrin/p53/SLC7A11/GPX4 signaling pathway, indicating that gankyrin may be a useful biomarker for predicting TNBC prognosis or a potential therapeutic target.

Dataset Information

IFNγ synergies with cold atmospheric plasma in triggering colorectal cancer cell ferroptosis via the IFNγ/IFNR2/APC/TCF4/GPX4 axis.

Publications

IFNγ synergies with cold atmospheric plasma in triggering colorectal cancer cell ferroptosis via the IFNγ/IFNR2/APC/TCF4/GPX4 axis.

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