A Mutual Interaction Between GSTP1 and p53 Improves the Drug Resistance and Malignant Biology of Pancreatic Cancer

Cancer Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Glutathione S-transferase P1 (GSTP1), a classic tumor biomarker, plays controversial role in cancer progression. However, its specific pancreatic (PC) has rarely been investigated. In the present study, we investigated function and relationship between GSTP1 mutant/wild-type p53 (mtp53/wtp53) PC vitro vivo. Compared with paired adjacent normal pancreas tissue, was downregulated which closely correlated lymph node metastasis, Union for International Cancer Control (UICC) stage, better outcome of patients, processes dependent on wtp53 rather than mtp53. Moreover, mutual regulation found cells. overexpression inhibited cell proliferation chemotherapy resistance via wtp53/p21 Bax/Bcl2 signaling, significantly reversed by silencing, vice versa. Similarly, coordination regulated invasion migration cells, accompanied changes epithelial-mesenchymal transition (EMT) signaling (E-cad, ZO-1 MMP9). growth liver metastasis vivo, as did high low ki67 expression. Interestingly, not coimmunoprecipitate either mtp53 or vitro. protein, transcription factor, could bind to DNA promoter transactivate mRNA expression demonstrated Chip assay. Additionally, promoted translocation into nucleus but These results suggest that positive feedback significant proliferation, drug resistance, PC.

Язык: Английский

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ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression

Cell Death and Differentiation, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

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Tumor cell-intrinsic BIN1 deficiency promotes the immunosuppression and impedes ferroptosis of non-small cell lung cancer via G3BP1-mediated degradation of STAT1

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Background Tumors often evade immune surveillance by limiting T cell infiltration. In non-small lung cancer (NSCLC), increased infiltration of CD8⁺ cells is associated with a favorable response to immunotherapy. While BIN1 recognized as tumor suppressor gene, its role in shaping the microenvironment NSCLC has yet be fully clarified. Methods To investigate relationship between expression and CD8⁺T NSCLC, we performed comprehensive data analysis utilizing clinical information from patients. levels tissues were evaluated, their correlation patient survival outcomes was examined. Loss-of-function strategies targeting applied syngeneic mouse models assess functional significance. Tumor growth monitored, populations analyzed terms frequency functionality through mass cytometry flow techniques. Cytokine secretion profiled using multiplex assays. Additionally, RNA sequencing, immunoprecipitation-mass spectrometry, molecular docking employed confirm direct interactions cytokine-encoding genes. Finally, regulatory ferroptosis explored metabolomics analysis, ROS measurement, MDA detection. Results We observed that downregulated tissues, reduced strongly advanced disease progression poor prognosis. Bioinformatics human samples revealed positive Furthermore, prognostic impact on patients linked level models, knockout significantly inhibited impaired cytotoxic function, facilitating evasion. Mechanistically, demonstrated directly interacts G3BP1, stabilizes G3BP1. This, turn, promotes STAT1 degradation reduces cell-recruiting chemokines such CXCL10 CCL5. our findings reveal influences G3BP1/STAT1/GSH pathway, thereby regulating proliferation, migration, invasion. Conclusion This study highlights crucial BIN1/G3BP1/STAT1/CD8⁺ tumor-infiltrating lymphocyte signaling pathway mechanisms fundings lay foundation for development BIN1-targeted therapies aimed at improving immunogenicity transforming immunologically “cold” into more responsive disease.

Язык: Английский

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CIAPIN1 attenuates ferroptosis via regulating PI3K/AKT pathway in LPS-induced podocytes

BMC Nephrology, Год журнала: 2025, Номер 26(1)

Опубликована: Апрель 21, 2025

Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a crucial anti-apoptotic protein; however, its role and associated molecular pathways in ferroptosis remain largely unexplored. This study aimed to investigate the effects of CIAPIN1 on lipopolysaccharide (LPS)-induced podocytes underlying phenomenon. In this study, we recruited 50 sepsis patients (aged 56.63 ± 10.33) with acute kidney injury (AKI), without AKI, healthy controls. We established an vitro model LPS-induced MPC5 podocytes. RT-qPCR Western blotting were used evaluate mRNA protein expression, respectively. Serum downregulated septic AKI overexpression (OE-CIAPIN1) attenuated cell proliferation OE-CIAPIN1 elevated phosphorylated phosphoinositide 3-kinase (p-PI3K; p85, Tyr458) kinase B (p-Akt; Ser473) levels significantly synaptopodin remarkably lowered desmin expression cells. contrast, treatment PI3K/Akt pathway inhibitor, LY294002, reversed Additionally, reduced malondialdehyde (MDA) content Fe2 + concentration lysate cells, while elevating MDA by LY294002 treatment. Furthermore, increased ferroptosis-related proteins, including solute carrier family 7 member 11 (SLC7A11) glutathione peroxidase 4 (GPX4), which was These results suggest that serum inhibits regulating PI3K/AKT signaling pathway.

Язык: Английский

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JS-K induces ferroptosis in renal carcinoma cells by regulating the c-Myc-GSTP1 Axis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Май 8, 2025

JS-K is a precursor drug of nitric oxide (NO) and inhibits tumor growth through various mechanisms. Ferroptosis, form cell death closely related to lipid peroxidation, increasingly being recognized for its role in cancer biology. However, the relevance ferroptosis anti-tumor effects yet be defined. The cytotoxic erastin were evaluated renal carcinoma (RCC) lines normal human epithelial cells. Cell viability intracellular levels ferrous ions, glutathione (GSH), peroxides, malondialdehyde (MDA) measured using standard vitro assays. expression specific proteins analyzed by western blotting. Subcutaneous xenografts RCC established nude mouse model, assessed histological immunohistochemical methods. Erastin selectively inhibited cells without affecting In addition, induced reducing cellular GSH levels, increasing elevating ion neutralized N-acetylcysteine (NAC). At molecular level, downregulated GSTP1 blocking transcription factor c-Myc. Finally, model inducing ferroptosis. induces depleting inhibition c-Myc-GSTP1 axis.

Язык: Английский

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Tumor cell-intrinsic BIN1 deficiency promotes the immunosuppression and impedes ferroptosis of non-small cell lung cancer via G3BP1-mediated degradation of STAT1

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Май 9, 2025

Язык: Английский

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AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells

Heliyon, Год журнала: 2024, Номер 10(14), С. e34397 - e34397

Опубликована: Июль 1, 2024

Multiple myeloma (MM) is an incurable malignancy of plasma cells that sensitive to T-5224, AP-1 inhibitor. Previous study indicated T-5224 inhibits proliferation and induces apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated ferroptosis induced by MM. Therefore, we further mechanism which kills We observed exhibits antimyeloma properties both vitro vivo. T-5224-induced cell death was reversed ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels key regulators GPX4 SLC7A11 were decreased Furthermore, reduced phosphorylation PI3K AKT signaling pathway components, ultimately causing death. Using 740 Y–P, a activator, Fer-1, inhibitor, discovered through PI3K/AKT pathway. Bortezomib (BTZ), FDA-approved drug for treatment, can administered combination with other agents. evaluated synergistic effect BTZ combined inhibitors on Our findings provide better theoretical basis potential new perspective treatment.

Язык: Английский

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Multi-species genome-wide CRISPR screens identify conserved suppressors of cold-induced cell death

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 26, 2024

Cells must adapt to environmental changes maintain homeostasis. One of the most striking adaptations is entry into hibernation during which core body temperature can decrease from 37°C as low at 4°C. How mammalian cells, evolved optimally function within a narrow range temperatures, this profound in remains poorly understood. In study, we conducted first genome-scale CRISPR-Cas9 screen cells derived Syrian hamster, facultative hibernator, well human investigate genetic basis cold tolerance hibernator and non-hibernator an unbiased manner. Both screens independently revealed glutathione peroxidase 4 (GPX4), selenium-containing enzyme, associated proteins critical for tolerance. We utilized pharmacological approaches demonstrate that GPX4 active its catalytic activity required Furthermore, show role suppressor cold-induced cell death extends across hibernating species, including 13-lined ground squirrels greater horseshoe bats, highlighting evolutionary conservation mechanism This study identifies central modulator advances our understanding mechanisms by mitigate cold-associated damage-one common challenges faced organisms nature.

Язык: Английский

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Targeting ferroptosis by natural products in pathophysiological conditions

Archives of Toxicology, Год журнала: 2024, Номер 98(10), С. 3191 - 3208

Опубликована: Июль 10, 2024

Язык: Английский

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Cerebroprotein hydrolysate-I ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via the p53/SAT1/ALOX15 signalling pathway

European Journal of Pharmacology, Год журнала: 2024, Номер 979, С. 176820 - 176820

Опубликована: Июль 18, 2024

Ferroptosis, an iron-dependent lipid peroxidation-driven cell death pathway, has been linked to the development of Alzheimer's disease (AD). However, role ferroptosis in pathogenesis AD remains unclear. Cerebroprotein hydrolysate-I (CH–I) is a mixture peptides with neurotrophic effects that improves cognitive deficits and reduces amyloid burden. The present study investigated ferroptosis-induced signalling pathways neuroprotective CH–I brains transgenic mice. Seven-month-old male APPswe/PS1dE9 (APP/PS1) mice were treated intraperitoneal injections saline for 28 days. Morris water maze test was used assess function. significantly improved attenuated beta-amyloid (Aβ) aggregation tau phosphorylation hippocampus APP/PS1 RNA sequencing revealed multiple genes pathways, including ferroptosis-related involved CH–I. increased levels peroxidation, ferrous ions, reactive oxygen species (ROS), altered expression (recombinant solute carrier family 7, member 11 (SLC7A11), spermidine/spermine N1-acetyltransferase 1 (SAT1) glutathione peroxidase 4 (GPX4)) alleviated after treatment. Quantitative real-time PCR western blotting performed investigate key p53/SAT1/arachidonic acid 15-lipoxygenase (ALOX15) pathway. p53/SAT1/ALOX15 pathway found be mediating ferroptosis, activation this suppressed by demonstrated against attenuating thus providing new targets

Язык: Английский

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