scholarly journals Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifei Qin ◽  
Zhuo Pei ◽  
Zhuan Feng ◽  
Peng Lin ◽  
Shijie Wang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Cell ◽  
Critical Role ◽  
Death Process ◽  
Hippo Signaling ◽  
Epithelial Tumor ◽  
Sorafenib Treatment ◽  
Potential Biomarker ◽  
Hcc Cells

Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies.

scholarly journals APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.

Haematologica ◽  
2021 ◽  
Author(s):  
Rudy Birsen ◽  
Clement Larrue ◽  
Justine Decroocq ◽  
Natacha Johnson ◽  
Nathan Guiraud ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Lipid Peroxides ◽  
Death Process ◽  
Glutathione Biosynthesis ◽  
Acute Myeloid

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia. APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.

scholarly journals Mitochondria: Regulators of Cell Death and Survival

2002 ◽  
Vol 2 ◽  
pp. 1569-1578 ◽  
Author(s):  
David J. Granville ◽  
Roberta A. Gottlieb
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Death Process ◽  
Protein Protein Interactions ◽  
Ionic Changes ◽  
A Cell ◽  
Cyt C

The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.

scholarly journals Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA

2019 ◽  
Vol 110 (9) ◽  
pp. 2856-2866 ◽  
Author(s):  
Kazuo Tomita ◽  
Yuko Takashi ◽  
Yuya Ouchi ◽  
Yoshikazu Kuwahara ◽  
Kento Igarashi ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines

RelB silencing to reverse tamoxifen resistance by regulating GPx4 and ferroptosis in breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12513-e12513
Author(s):  
Zhi Xu ◽  
Jinhai Tang
Keyword(s):  
Breast Cancer ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Death Process ◽  
Enhancer Element ◽  
High Level

e12513 Background: Tamoxifen(Tam), as an essential therapeutic treatment of estrogen receptor(ER)-positive breast cancer(BCa), has been available for the past three decades. However, the induction of Tam resistance during therapy has indicated a significant challenge with regards to this agent. Tam could increase oxidative stress and induce cell death by regulating reactive oxygen species(ROS). Ferroptosis, a cell death process driven by the accumulation of iron-dependent lipid peroxides, has been induced by inactivation/depletion of glutathione peroxidases(GPxs). Our previous studies found that the expression level of RelB gene, a member of NF-κB family, is negatively correlated with ER targeted by Tam in BCa. Methods: The RelB level of BCa tumor tissues and the corresponding cell lines were examined by immunoblotting and western blot. The effects of Tam on cell viability were determined using colony survival and MTT assay. The ROS and oxygen consumption rates(OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. The lipid peroxidation level of cells was analyzed by immunofluorescence assay. The morphological changes of mitochondria were observed by transmission electron microscope. RelB binding to the NF-κB intronic enhancer region of the human GPx4 gene was determined using a ChIP assay. Accordingly, the effect of RelB on BCa Tam resistance was further validated using BCa mice xenograft models. Results: RelB was uniquely expressed at the high level in Tam resistance BCa tissues and cell lines. Down-regulation of RelB based on a CRISPR/Cas9 system remarkably sensitized resistance BCa cells to Tam. Treatment with SN52, a RelB inhibitor, illuminated the role of RelB in Tam-treated BCa cells. The high level of ROS and declination of mitochondrial respiration which induced by Tam were inhibited in resistance cells. Tam enhanced lipid peroxidation with concomitant non-apoptotic cell death, which are negatively regulated by GPx4 activity. In addition to GPx4 knockdown, deferoxamine was able to rescue Tam-induced cell death in BCa cells, verifying that Tam induces cell death partially through ferroptosis. Importantly, RelB upregulates GPx4 expression through binding to an NF-κB enhancer element located at the 5’-flanking region. Consistently, in vivo functional validation confirmed that RelB inhibition not only impairs tumor growth, but also inhibits Tam resistance in nude mice. Conclusions: RelB could inhibit ferroptosis which induced by hydroxyl radicals accumulation through upregulating GPx4 in BCa.

scholarly journals Ferroptosis and its facet in Cancer therapy

2021 ◽  
Vol 6 (1) ◽  
pp. 10-15
Author(s):  
Shreya Shreshtha
Keyword(s):  
Cell Death ◽  
Cell Therapy ◽  
Cancer Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Death Process ◽  
Cell Organelles ◽  
Clinical Role ◽  
Cell Death Process

Ferroptosis is a regulated process impelled by iron-dependent lipid peroxidation. It is a new type of cell destruction processes including apoptosis, autophagy and necrosis. It demonstrates mainly the contraction of mitochondria and expansion of mitochondrial membrane density which does not lead to any alteration in morphology. Due to the malfunctioning of ferroptosis several disorders arise which includes damage of one or more nerve which leads to numbness and muscle weakness whereas ischemia reperfusion injury, acute kidney failure and cancer also occurs. Also, ferroptosis is induced in large number of cancer cells through series of small molecules which helps in to bringing out this process. In scientific research and medicine many findings contribute in the chance of defeating cancer by genetic or pharmacological interference with ferroptosis cell death which is appealing for various researches. There are multiple pathways and cell organelles which plays a role in ferroptosis regulation. Ongoing studies on ferroptosis have demonstrated its role in humans though its mechanism is not yet clear. Recently, various studies have encouraged the role of this newly emerged cell death process and also showed some effective usage in the treatment of cancer. Here, we review the mitochondrial aspect of ferroptosis as well as discuss on the role of ferroptosis in Cancer cell therapy. We will also aim on the future scope of ferroptosis in the treatment of Cancer as well as discuss about the problems related to its clinical role which may trigger the cancer cell therapy.

miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy

Gut ◽  
2019 ◽  
Vol 69 (7) ◽  
pp. 1309-1321 ◽  
Author(s):  
Wen-Ping Xu ◽  
Jin-Pei Liu ◽  
Ji-Feng Feng ◽  
Chang-Peng Zhu ◽  
Yuan Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Sorafenib Treatment ◽  
Transmission Electron ◽  
Reporter Assays ◽  
Hcc Cells

ObjectiveAutophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis.DesignGain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.ResultsThe expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.ConclusionsDysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

scholarly journals High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

2021 ◽  
Author(s):  
Jianjun Xu ◽  
Zhe Su ◽  
Xiang Cheng ◽  
Shaobo Hu ◽  
Wenjie Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
T Cell Activation ◽  
Critical Role ◽  
Treatment Result ◽  
Tunel Staining ◽  
Sorafenib Treatment ◽  
Adaptive Resistance ◽  
Hcc Cells

Abstract Background Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified. Methods By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1–6 were treated with DC661 against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blotting, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1. Results Wefound that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating xenograft models in immunized mice. Conclusions Our findings suggested that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

scholarly journals AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC Cells Through Nrf2/xCT Pathway

2021 ◽  
Author(s):  
Hao Feng ◽  
Yi Liu ◽  
Yuhan Gan ◽  
Mengke Li ◽  
Rui Liu ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Radiation Sensitivity ◽  
Carcinoma Cells ◽  
Luciferase Reporter ◽  
Mrna And Protein Expression ◽  
Radiation Induced ◽  
Hepatic Cell Lines ◽  
Hcc Cells

Abstract Background: Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, however, how IR-induced ferroptosis is regulated in Hepatocellular carcinoma cells (HCC) remains largely unknown. We have previously found that adiponectin receptor 1(AdipoR1) might be a prognostic biomarker for HCC after stereotactic body radiotherapy (SBRT). In this study, we aimed to elucidate the roles of AdipoR1 in radiation-induced Ferroptosis of HCC.Methods: Human HCC cell line MHCC-97H and HepG2 and human hepatic cell lines LO2 were tested. qRT-PCR and western blotting were used to detect mRNA and protein expression respectively, colony formation assay was used to evaluate the radiosensitivity and flow cytometry was used to assess lipid peroxidation and cell death. Dual-Luciferase Reporter assay system was used to detect the transcription activity. Results: Ionizing Radiation (IR) upregulated the expression of AdipoR1 in HCC cells and AdipoR1 knockdown could promote radiation sensitivity of HCC cells. AdipoR1 knockdown could decrease the expression of Nrf2 and Nrf2 protein stability. Nrf2 could bind to xCT promoter and promoted the transcription and expression of xCT. AdipoR1 knockdown increased significantly lipid peroxidation and ferroptosis induced by IR or Erastin respectively, which could be abolished by overexpression of Nrf2 and xCT.Conclusion: AdipoR1 knockdown can promote radiation sensitivity of HCC cells; AdipoR1 regulates IR-induced cell death by AdipoR1-Nrf2-xCT pathway.

The role of usnic acid-induced apoptosis and autophagy in hepatocellular carcinoma

2018 ◽  
Vol 38 (2) ◽  
pp. 201-215 ◽  
Author(s):  
B Yurdacan ◽  
U Egeli ◽  
G Guney Eskiler ◽  
IE Eryilmaz ◽  
G Cecener ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Usnic Acid ◽  
Genetic Profile ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cell Type ◽  
Hcc Cells

Usnic acid (UA) is a multifunctional bioactive lichen secondary metabolite with potential anti-cancer properties. Although the promising therapeutic effects of UA have been investigated in different cancer cell lines, the mechanism driving UA-induced cell death has yet to be elucidated. As the type of cell death (apoptosis or autophagy) induced by UA may vary depending on the cancer cell type, we first studied the cytotoxic effects of UA in HEPG2 (HBV(−)) and SNU-449(HBV(+)) hepatocellular carcinoma (HCC) cell lines. HCC cell viability was considerably reduced in a dose-dependent manner at 12, 24, and 48 h after treatment with UA ( p < 0.05). However, SNU-449 cells were more sensitive to UA than HEPG2 cells. UA also induced apoptotic cell death in HCC cells with cell cycle arrest at G0/G1 and G2/M phase depending on the genetic profile of each cell type. On the other hand, we observed acidic vesicular organelles in HCC cells after 36 h of UA treatment. Taken together, these findings suggest that UA stimulates apoptosis and autophagy in HEPG2 and SNU-449 cells without damaging normal control cells. Thus, UA might be a potential therapeutic compound for HCC treatment. However, there is a need for further studies investigating the death-promoting or preventing roles for autophagy and the molecular signaling mechanisms induced by UA treatment.

scholarly journals Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lian-Jiu Su ◽  
Jia-Hao Zhang ◽  
Hernando Gomez ◽  
Raghavan Murugan ◽  
Xing Hong ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Critical Role ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Chain Reactions ◽  
Know How ◽  
Different Types ◽  
Highly Evolved

Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and conserved mechanism is based on an excess of ROS which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. A highly evolved sophisticated antioxidant system exists that acts to protect the cells from oxidative damage. In this review, we discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipid peroxidation initiate apoptosis and autophagy in current models. We also discussed the mechanism of lipid peroxidation during ferroptosis, and we summarized lipid peroxidation in pathological conditions of critical illness. We aim to bring a more global and integrative sight to know how different ROS-induced lipid peroxidation occurs among apoptosis, autophagy, and ferroptosis.

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