Damage-associated molecular pattern molecules (DAMPs) are endogenous danger signals that alert the innate immune system and shape the inflammation response to cell death. However, the release and ...activity of DAMPs in ferroptosis, a recently identified form of regulated necrosis characterized by iron overload and lipid peroxidation, still remain poorly understood. Here, we demonstrate that HMGB1 is a DAMP released by ferroptotic cells in an autophagy-dependent manner. Both type I and II ferroptosis activators, including erastin, sorafenib, RSL3, and FIN56, induce HMGB1 release in cancer and noncancer cells. In contrast, genetic ablation (using ATG5−/− or ATG7−/− cells) or pharmacologic inhibition (the administration of bafilomycin A1 or chloroquine) of autophagy was found to block ferroptosis activator-induced HMGB1 release. Mechanically, autophagy-mediated HDAC inhibition promotes HMGB1 acetylation, resulting in HMGB1 release in ferroptosis. Moreover, AGER, but not TLR4, is required for HMGB1-mediated inflammation in macrophages in response to ferroptotic cells. These studies suggest that HMGB1 inhibition might have some potential therapeutic effects in ferroptosis-associated human disease.
•Ferroptosis activators induce HMGB1 release.•Autophagy promotes HMGB1 release in ferroptosis.•Autophagy promotes HMGB1 acetylation in ferroptosis.•HMGB1-AGER pathway mediates inflammation response in ferroptosis.
Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system Xc–. However, key regulators of system Xc– activity in ...ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system Xc– activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system Xc– inhibitors (e.g., erastin, sulfasalazine, and sorafenib), but not other ferroptosis inducers including RSL3, FIN56, and buthionine sulfoximine. Mechanistically, AMP-activated protein kinase (AMPK)-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation and lipid peroxidation. Inhibition of PRKAA/AMPKα by siRNA or compound C diminishes erastin-induced BECN1 phosphorylation at S93/96, BECN1-SLC7A11 complex formation, and subsequent ferroptosis. Accordingly, a BECN1 phosphorylation-defective mutant (S90,93,96A) reverses BECN1-induced lipid peroxidation and ferroptosis. Importantly, genetic and pharmacological activation of the BECN1 pathway by overexpression of the protein in tumor cells or by administration of the BECN1 activator peptide Tat-beclin 1, respectively, increases ferroptotic cancer cell death (but not apoptosis and necroptosis) in vitro and in vivo in subcutaneous and orthotopic tumor mouse models. Collectively, our work reveals that BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis.
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•BECN1 is required for system Xc–-inhibitor-induced ferroptosis•BECN1 inhibits system Xc– activity through directly binding to SLC7A11•AMPK is required for BECN1 phosphorylation in ferroptosis•BECN1 contributes to the anticancer activity of ferroptosis in vivo
Song et al. find that BECN1 promotes ferroptosis by directly blocking system Xc– activity via binding to its core component SLC7A11. This pathway is different from the previously identified function of BECN1 as a positive regulator of autophagy via directly activating PtdIns3K activity via binding to its core component PIK3C3.
Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of ...gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4−/− mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.
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•Gpx4 deficiency in myeloid cells increases severity of polymicrobial sepsis in mice•Caspase-11-dependent pyroptosis mediates septic death in Gpx4Mye−/− mice•GPX4 decreases lipid peroxidation to block PLCG1-mediated GSDMD activity and pyroptosis•Antioxidant activity of vitamin E promotes survival during sepsis in Gpx4Mye−/− mice
Kang et al. demonstrate that glutathione peroxidase 4 (GPX4) serves a protective role in mice undergoing septic shock. Myeloid-specific deficiency of Gpx4 coordinates lipid peroxidation-dependent caspase-11 activation and gasdermin D-mediated pyroptosis during polymicrobial sepsis. Vitamin E administration reverses Gpx4Mye−/− susceptibility, thereby revealing a potential target for therapeutic intervention for lethal infection.
Pancreatic cancer is an aggressive malignancy with changes in the tumor microenvironment. Here, we demonstrate that PINK1 and PARK2 suppressed pancreatic tumorigenesis through control of ...mitochondrial iron-dependent immunometabolism. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2 accelerates mutant Kras-driven pancreatic tumorigenesis. PINK1-PARK2 pathway-mediated degradation of SLC25A37 and SLC25A28 increases mitochondrial iron accumulation, which leads to the HIF1A-dependent Warburg effect and AIM2-dependent inflammasome activation in tumor cells. AIM2-mediated HMGB1 release further induces expression of CD274/PD-L1. Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic depletion of Hif1a or Aim2 in pink1−/− and park2−/− mice confers protection against pancreatic tumorigenesis. Low PARK2 expression and high SLC25A37 and AIM2 expression are associated with poor prognosis in patients with pancreatic cancer. These findings suggest that disrupted mitochondrial iron homeostasis may contribute to cancer development and hence constitute a target for therapeutic intervention.
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•PINK1 and PARK2 suppress oncogenic Kras-driven pancreatic tumorigenesis•Mitochondrial iron accumulation contributes to pancreatic tumorigenesis•HIF1A is required for the Warburg effect in pancreatic tumorigenesis•AIM2-mediated HMGB1 release promotes pancreatic tumorigenesis
Li et al. demonstrate in mouse models that Pink1 and Park2 deficiency accelerates pancreatic tumorigenesis through mitochondrial iron-dependent immunometabolic dysfunction. These findings shed light on how the autophagy pathway controls iron homeostasis and could have implications for the development of strategies to target mitochondrial iron metabolism in pancreatic cancer.
The effects of cigarette smoking on male semen quality are controversial, and the molecular mechanisms underlying how cigarette smoking affects semen quality are not clear yet.
In this study, semen ...samples from 70 heavy smokers and 75 non-smokers receiving infertility treatment were included. Basic semen parameters in non-smokers and heavy smokers were evaluated. Levels of glutathione (GSH), lipid reactive oxygen species (ROS), iron and GSH-dependent peroxidase 4 (GPX4) protein level were observed in human seminal plasma and in GC-2Spd cells exposed to cigarette smoke condensate (CSC).
Heavy smokers had significantly higher abnormalities (sperm viability and sperm progressive motility) than non-smoking counterparts. Comparing non-smokers group, GSH level was reduced in the group of heavy smokers (P < 0.05). However, the level of lipid ROS and iron were significantly increased (P < 0.05). Besides, GSH level was reduced following treatment with CSC for 24 h, while lipid ROS and iron levels were increased (P < 0.05). However, the levels were reduced after being co-cultured with Ferrostatin-1 (Fer-1) (P < 0.05). The level of GPX4 protein was reduced after being treated with CSC in 24 h, and increased after being co-cultured with Fer-1(P < 0.05).
Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affect semen quality.
Metastasis associated in lung adenocarcinoma transcript-1 (MALAT-1) is overexpressed during cancer progression and promotes cell migration and invasion in many solid tumors. However, its role in ...ovarian cancer remains poorly understood.
Expressions of MALAT-1 were detected in 37 normal ovarian tissues and 45 ovarian cancer tissues by reverse transcription polymerase chain reaction (RT-PCR). Cell proliferation was observed by CCK-8 assay; Flow cytometry was used to measure cell cycle and apoptosis; Cell migration was detected by transwell migration and invasion assay. In order to evaluate the function of MALAT-1, shRNA combined with DNA microarray and Functional enrichment analysis were performed to determine the transcriptional effects of MALAT-1 silencing in OVCAR3 cells. RNA and protein expression were measured by qRT-PCR and Western blotting, respectively.
We found that upregulation of MALAT-1 mRNA in ovarian cancer tissues and enhanced MALAT-1 expression was associated with FIGO stage. Knockdown of MALAT-1 expression in OVCAR3 cells inhibited cell proliferation, migration, and invasion, leading to G0/G1 cell cycle arrest and apoptosis. Overexpressed MALAT-1 expression in SKOV3 cells promoted cell proliferation, migration and invasion. Downregulation of MALAT-1 resulted in significant change of gene expression (at least 2-fold) in 449 genes, which regulate proliferation, cell cycle, and adhesion. As a consequence of MALAT-1 knockdown, MMP13 protein expression decreased, while the expression of MMP19 and ADAMTS1 was increased.
The present study found that MALAT-1 is highly expressed in ovarian tumors. MALAT-1 promotes the growth and migration of ovarian cancer cells, suggesting that MALAT-1 may be an important contributor to ovarian cancer development.
Ovarian carcinoma is one of the most aggressive gynecological malignant neoplasms and makes up 25-30% of all cancer cases of the female genital tract. Currently, resistance to traditional ...chemotherapy is a great challenge for patients with Epithelial ovarian cancer (EOC). Therefore, identifying novel agents for EOC treatment is essential and urgent.
MTS assay was used to analyze the cell viability and proliferation of cancer cells. Flow cytometry was employed to analyze cell cycle distribution and cell apoptosis. Protein signaling pathways were detected by western blot and immunohistochemical staining. Nude mouse experiment was performed to test the in vivo effect of platinum pyrithione (PtPT).
PtPT is a chemically well-characterized synthetic complex of platinum that potently inhibits proteasome-associated deubiquitinases USP14 and UCHL5 activity and shows selective cytotoxicity to multiple cancer cells without damaging DNA. We found that PtPT significantly accumulated ubquitinated-proteins and suppressed the proliferation of multiple EOC cells. Additionally, PtPT induced G2 phase arrest and apoptosis in both A2780 and SKOV3 cells. More importantly, animal experiments showed that PtPT dramatically suppressed the growth of EOC xenografts without obvious side effects.
These results suggest that through proteasome inhibition, PtPT significantly suppressed the proliferation of EOC in vitro and in vivo and could be developed as a novel agent for EOC treatment in the future.
Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the ...involvement of the female genital tract
species in gynecological cancer via indoleacrylic acid (IAA). IAA production from
species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on T
and T
cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically,
species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by
species transplantation, and the intratumoral injection of a conditioned medium from
cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the T
proportion and decreased the M1/M2 ratio. Clinically,
was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine
dysbiosis and provides a potential rationale for the role of
species in immune tolerance induction in type I endometrial cancer.
The aims of this study were to investigate the functions of GAS5 as a tumor suppressor in cervical cancer and explore the mechanism.
The expression of GAS5 and microRNA 21 (miR-21) was detected in ...primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. We identified the interaction of GAS5 and miR-21 by quantitative polymerase chain reaction, Western blot, and dual-luciferase reporter assay. We also studied the functions of GAS5 in proliferation, apoptosis, migration, and invasion in cervical cancer cells in vitro and vivo. Finally, the impact of GAS5 on cisplatin resistance and its mechanism in cervical cancer cells was also identified.
The expression of GAS5 and miR-21 was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. GAS5, which is a tumor suppressor playing roles in inhibiting the malignancy of cervical cancer cells, including proliferation in vivo and vitro, migration, and invasion, has a low expression in cervical cancer tissue and cervical cancer cell lines, whereas miR-21 expression is high. GAS5 significantly decreased the expression of miR-21, and there is a reciprocal repression of gene expression between GAS5 and miR-21. Besides, most importantly, we found that high expression of GAS5 and low expression of miR-21 can enhance the sensitivity of SiHa/cDDP cancer cells to cisplatin. A further experiment for identifying the mechanism of cisplatin resistance by GAS5 showed that GAS5 can not only regulate phosphatase and tensin homolog through miR-21 but also influence the phosphorylation of Akt.
Our results indicate that GAS5 is a direct target of miR-21 and can predict the clinical staging of cervical cancer. Most importantly, GAS5 can also influence cisplatin resistance in cervical cancer via regulating the phosphorylation of Akt. All of these suggest that GAS5 may be a novel therapeutic target for treating cervical cancer.
Elucidating the mechanism for the high metastasis capacity of Endometrial cancer (EC) is crucial to improve treatment outcomes of EC. We have recently reported that nicotinamide N-methyltransferase ...(NNMT) is overexpressed in EC, especially in EC, and predicts poor survival of chemotherapy patients. Here, we aimed to determine the function and mechanism of NNMT on metastasis of EC. Additionally, analysis of public datasets indicated that NNMT is involved in cholesterol metabolism. In vitro, NNMT overexpression promoted migration and invasion of EC by reducing cholesterol levels in the cytoplasm and cell membrane. Mechanistically, NNMT activated ABCA1 expression, leading to cholesterol efflux and membrane fluidity enhancement, thereby promoting EC's epithelial-mesenchymal transition (EMT). In vivo, the metastasis capacity of EC was weakened by targeting NNMT. Our findings suggest a new molecular mechanism involving NNMT in metastasis, poor survival of EC mediated by PP2A and affecting cholesterol metabolism.
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