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Journal ArticleDOI: 10.1093/ABBS/GMAA180

Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer.

02 Mar 2021-Acta Biochimica et Biophysica Sinica (Oxford Academic)-Vol. 53, Iss: 3, pp 333-341
Abstract: Metformin is a widely prescribed hypoglycemic drug. Many studies have shown its anti-cancer properties. In the present study, we aimed to explore the effect of metformin on breast cancer and clarify the underlying mechanism. Our results showed that metformin induced ferroptosis in MDA-MB-231 cells through upregulating miR-324-3p expression. Overexpression of miR-324-3p inhibited cancer cell viability. miR-324-3p inhibitor promoted cell viability. Further studies showed that the effect of miR-324-3p was mediated by directly targeting glutathione peroxidase 4 (GPX4). miR-324-3p bound to the 3'-UTR of GPX4 and led to the downregulation of GPX4. In vivo studies showed that metformin induced ferroptosis by upregulating miR-324-3p in the xenograft model of breast cancer in mice. Our study suggested that metformin promotes ferroptosis of breast cancer by targeting the miR-324-3p/GPX4 axis. Metformin could act as a potential anti-cancer agent through the induction of ferroptosis.

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Topics: Metformin (53%)
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6 results found


Open accessJournal ArticleDOI: 10.3390/CANCERS13184576
Hung-Yu Lin1, Hung-Yu Lin2, Hui-Wen Ho1, Yen-Hsiang Chang3  +3 moreInstitutions (3)
12 Sep 2021-Cancers
Abstract: Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

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1 Citations


Open accessPosted ContentDOI: 10.21203/RS.3.RS-855955/V1
09 Sep 2021-
Abstract: Background:Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown.Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. Methods:In this study, erastin was used to induce ferroptosis in CRC cells. Cell viability and apoptosis were assessed by CCK-8 and colony formation assayand annexin V/propidium iodide staining, respectively. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. Unfolded protein response-related proteins and GPX4 protein were analyzed by western blotting. The CRC datasetswere analyzed using the R software, GEPIA2 and TIMER2.0. Results:The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increasedduring ferroptosis. HSPA5 was found to attenuateerastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bounddirectly to GPX4 andthe interaction between HSPA5 and GPX4increased when treated with erastinfor a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to immune microenvironment in CRC patients.Conclusion:Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.

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Open accessJournal ArticleDOI: 10.1016/J.DLD.2021.10.003
Le Bao1, Pengfei Li, Hongying Zhao, Long Chen  +3 moreInstitutions (1)
Abstract: Background Pseudogenes are dysfunctional copies of protein-coding genes that showed critical regulatory roles during carcinogenesis. Plasminogen like A (PLGLA) is a transcribed unprocessed pseudogene and biasedly expressed in liver. But its function has not been studied in hepatocellular carcinoma (HCC). Aims We aimed to explore the role of PLGLA in HCC. Methods The expression of PLGLA and its association with pathological features in HCC patients was analyzed using The Cancer Genome Atlas (TCGA) datasets. Quantitative reverse transcription PCR (qRT-PCR) was used to validate PLGLA level in HCC tissue samples and cell lines. Gain-of-function experiments in vitro and in vivo were employed to assess the impact of PLGLA on HCC cell proliferation, migration and invasion. Luciferase reporter assay and RNA pull-down assay were conducted to confirm the interaction among PLGLA, miR-324–3p and GLYATL1. Results PLGLA expression was significantly downregulated in HCC tissues and cell lines. Furthermore, low PLGLA expression was positively associated with tumor progression and poor prognosis. PLGLA restoration markedly suppressed cell proliferation, migration and invasion. Mechanistically, PLGLA could competitively bind to miR-324–3p and acted as a competitive endogenous RNA (ceRNA) to enhance GLYATL1 expression. Conclusions Our results established a novel tumor suppressive role of PLGLA in HCC pathogenesis and highlighted its potential as a therapeutic target for HCC treatment.

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Open accessJournal ArticleDOI: 10.3389/FCELL.2021.748925
Zhi-Zhou Shi1, Hao Tao1, Ze-Wen Fan1, Sheng-Jie Song1  +1 moreInstitutions (1)
Abstract: Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and apoptosis inducing factor mitochondria associated 2 (AIFM2) are the key regulators in ferroptosis. However, the expression patterns and prognostic roles of these genes in pan-cancer are still largely unclear. The expression patterns and prognostic roles of SLC7A11, GPX4, and AIFM2 and the relationships between the expression levels of these genes and immune infiltration levels in pan-cancer were analyzed by using TIMER, gene expression profiling interactive analysis (GEPIA), Oncomine, and Kaplan-Meier databases. Our results showed that both SLC7A11 and GPX4 were overexpressed in colorectal cancer, and SLC7A11 was overexpressed in lung cancer. High levels of SLC7A11 and AIFM2 were significantly linked with the shortened disease-free survival and overall survival (OS) in adrenocortical carcinoma (ACC), respectively. And high expression of SLC7A11, GPX4, and AIFM2 were significantly correlated with the shortened OS of acute myeloid leukemia patients. In esophageal carcinoma (ESCA), GPX4 expression was significantly associated with the infiltration of macrophage and myeloid dendritic cell, and AIFM2 expression was significantly associated with the infiltration of CD4+ T cell. Importantly, GPX4 expression was positively correlated with the expression levels of monocyte markers (CD14 and CD115) and M2 macrophage markers (VSIG4 and MS4A4A) both in ESCA and in head and neck squamous cell carcinoma (HNSC). In summary, SLC7A11, GPX4, and AIFM2 are dysregulated in many types of cancers, and are candidate prognostic biomarkers for many types of cancers, and can be used to evaluate the infiltration of immune cells in tumor tissues.

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Open accessJournal ArticleDOI: 10.3390/IJMS22179453
Abstract: Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.

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Topics: AMPK (64%), Metformin (55%), Necroptosis (54%) ... show more

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48 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2012.03.042
25 May 2012-Cell
Abstract: Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.

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Topics: Programmed cell death (53%), SLC7A11 (52%), Cancer cell (50%) ... show more

3,349 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2017.09.021
05 Oct 2017-Cell
Abstract: Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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1,559 Citations


Journal ArticleDOI: 10.1200/JCO.2007.14.4287
Abstract: Purpose To determine whether breast cancer subtype is associated with outcome after breast-conserving therapy (BCT) consisting of lumpectomy and radiation therapy. Patients and Methods We studied 793 consecutive patients with invasive breast cancer who received BCT from July 1998 to December 2001. Among them, 97% had pathologically negative margins of resection, and 90% received adjuvant systemic therapy. No patient received adjuvant trastuzumab. Receptor status was used to approximate subtype: estrogen receptor (ER) or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 negative = luminal A; ER+ or PR+ and HER-2+ = luminal B; ER–and PR –and HER-2+ = HER-2; and ER–and PR –and HER-2–= basal. Competing risks methodology was used to analyze time to local recurrence and distant metastases. Results Median follow-up was 70 months. The overall 5-year cumulative incidence of local recurrence was 1.8% (95% CI, 1.0 to 3.1); 0.8% (0.3, 2.2) for luminal A, 1.5% (0.2, 10) for luminal B, 8....

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Topics: Breast cancer (59%), Lumpectomy (57%), Estrogen receptor (56%) ... show more

737 Citations


Journal ArticleDOI: 10.1016/J.MOLMED.2006.10.006
Ramiro Garzon1, Muller Fabbri1, Amelia Cimmino1, George A. Calin1  +1 moreInstitutions (1)
Abstract: MicroRNAs are small non-coding RNAs of 19-24 nucleotides in length that downregulate gene expression during various crucial cell processes such as apoptosis, differentiation and development. Recent work supports a role for miRNAs in the initiation and progression of human malignancies. Large high-throughput studies in patients revealed that miRNA profiling have the potential to classify tumors with high accuracy and predict outcome. Functional studies, some of which involve animal models, indicate that miRNAs act as tumor suppressors and oncogenes. Here, we summarize miRNA-profiling studies in human malignancies and examine the role of miRNAs in the pathogenesis of cancer. We also discuss the implications of these findings for the diagnosis and treatment of cancer.

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Topics: microRNA (53%), Cancer (53%), Gene expression profiling (50%)

731 Citations


Open accessJournal ArticleDOI: 10.1016/J.CANEP.2012.02.007
Danny R. Youlden1, Susanna M. Cramb1, Nathan Dunn2, Jennifer Muller2  +2 moreInstitutions (2)
Abstract: Background This paper presents the latest international descriptive epidemiological data for invasive breast cancer amongst women, including incidence, survival and mortality, as well as information on mammographic screening programmes. Results Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 and approximately 459,000 deaths were recorded. Incidence rates were much higher in more developed countries compared to less developed countries (71.7/100,000 and 29.3/100,000 respectively, adjusted to the World 2000 Standard Population) whereas the corresponding mortality rates were 17.1/100,000 and 11.8/100,000. Five-year relative survival estimates range from 12% in parts of Africa to almost 90% in the United States, Australia and Canada, with the differential linked to a combination of early detection, access to treatment services and cultural barriers. Observed improvements in breast cancer survival in more developed parts of the world over recent decades have been attributed to the introduction of population-based screening using mammography and the systemic use of adjuvant therapies. Conclusion The future worldwide breast cancer burden will be strongly influenced by large predicted rises in incidence throughout parts of Asia due to an increasingly "westernised" lifestyle. Efforts are underway to reduce the global disparities in survival for women with breast cancer using cost-effective interventions.

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Topics: Relative survival (61%), Breast cancer (61%), Mortality rate (59%) ... show more

569 Citations