Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis

Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza, attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.

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“…5g ). 31 SAC preserved protein expression of ACO2 and NDUFS1, but the effect was blocked by Nfs1 knockdown (Fig. 5h ).…”

Section: Resultsmentioning

confidence: 93%

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Zeng

Pan

Zhan

et al. 2022

Sig Transduct Target Ther

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“…Pyroptosis, as a form of immunogenic cell death, is a potential tumor treatment strategy ( 8 , 9 , 16 , 22 , 23 ). Several promising small molecules and nanomaterials have been reported in different cancers, such as non-small cell lung carcinoma ( 24 – 26 ), colorectal cancer ( 12 , 27 – 29 ), hepatocellular carcinoma ( 30 – 32 ), breast cancer ( 33 – 36 ), melanoma ( 11 , 16 , 34 ), and glioblastoma ( 37 – 40 ). However, there have been only two studies on pyroptosis-induced therapy in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

et al. 2022

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BackgroundThe frequent emergence of drug resistance to chemotherapy is a major obstacle for the treatment of ovarian cancer. There is a need for novel drugs to fulfill this challenge. Pyroptosis-inducing drugs can inhibit tumor growth. However, their roles in ovarian cancer have not been demonstrated.MethodsWe tested the effectiveness of a novel drug, BI 2536, which we found in colorectal cancer. Cell proliferation, cell cycle, and drug-induced apoptosis and pyroptosis were tested. In vivo treatments were performed using a cell-derived xenograft model.ResultsBI 2536 significantly inhibited the proliferation of ovarian cancer cells and induced cell cycle arrest at the G2/M phases. After BI 2536 treatment, DNA fragmentation and PS exposure on the outside of apoptotic cells were detected. Moreover, the pyroptotic phenotype of ovarian cancer cells along with the release of LDH and HMGB1 were observed, indicating the leakage of cells. Western blot analysis verified that BI 2536 induced GSDME-mediated pyroptosis. Pyroptosis was abolished after additional treatment with Z-DEVD-FMK, a caspase-3 inhibitor. Thus, BI 2536 induced pyroptosis in ovarian cancer through the caspase-3/GSDME pathway. In vivo experiments further demonstrated the antitumoral effect and ability of BI 2536 to accumulate CD8+ T cells in ovarian cancer.ConclusionIn this study, we identified BI 2536 as an effective anti-ovarian cancer drug that inhibits proliferation, arrests the cell cycle, induces apoptosis and pyroptosis, and leads to the accumulation of CD8+ T cells in tumor sites. Drug-induced pyroptosis may have promising prospects for reducing side effects and activating immune responses.

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“…However, the specific mechanism is not yet clear. The latest in vitro and in vivo research results show that oxaliplatin-based oxidative stress enhance the phosphorylation level of serine residues of NFS1, which protect CRC cells in an S293 phosphorylation-dependent manner during oxaliplatin treatment ( Lin et al, 2022 ). While NFS1 deficiency synergizing with oxaliplatin by increasing the intracellular levels of ROS ( Lin et al, 2022 ).…”

Section: Ferroptosis Resistance In Tumor Cellsmentioning

confidence: 99%

System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

et al. 2022

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The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc−), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc−/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc−/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc−/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

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Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis

Cited by 152 publications

References 49 publications

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

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