Methylglyoxal Acts as a Tumor-Promoting Factor in Anaplastic Thyroid Cancer

Antognelli, Cinzia; Moretti, Sonia; Frosini, Roberta; Puxeddu, Efisio; Sidoni, Angelo; Talesa, Vincenzo Nicola

doi:10.3390/cells8060547

Cited by 50 publications

(53 citation statements)

References 57 publications

(111 reference statements)

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“…In line with these results, our study suggests that CA protects β-cells against MG-induced toxicity by increasing Glo-1 protein expression and enzyme activity. We also observed an increase in Nrf2 protein expression in the INS-1 cells pre-treated with CA, although a similar effect by another phytochemical, resveratrol has been described [32]. Thus, it is highly possible that the CA pre-treatment of INS-1 cells may increase Glo-1 protein expression and enzymatic activity via the Nrf2 signaling pathway.…”

Section: Discussionsupporting

confidence: 84%

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

Yoo

Hong

et al. 2020

Antioxidants

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To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic β-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 μM) for 48 h and then treated with 2 mM MG for 8 h. The effects of CA and MG on INS-1 cells were evaluated using the following: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; glyoxalase 1 (Glo-1) expression via Western blot and enzyme activity assays; Nrf-2, nuclear factor erythroid 2-related factor 2 protein expression via Western blot assay; reactive oxygen species (ROS) production assay; mRNA expression of mitochondrial dysfunction related components (UCP2, uncoupling protein 2; VDAC1, voltage-dependent anion-selective channel-1; cyt c, cytochrome c via quantitative reverse transcriptase-PCR; mitochondrial membrane potential (MMP); adenosine triphosphate (ATP) synthesis; glucose-stimulated insulin secretion (GSIS) assay. The viability of INS-1 cells was maintained upon pre-treating with CA before exposure to MG. CA upregulated Glo-1 protein expression and enzyme activity in INS-1 cells and prevented MG-induced ROS production. Mitochondrial dysfunction was alleviated by CA pretreatment; this occurred via the downregulation of UCP2, VDAC1, and cyt c mRNA expression and the increase of MMP and ATP synthesis. Further, CA pre-treatment promoted the recovery from MG-induced decrease in GSIS. These results indicated that CA could be employed as a therapeutic agent in diabetes due to its ability to prevent MG-induced development of insulin sensitivity and oxidative stress-induced dysfunction of β-cells.

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Section: Discussionsupporting

confidence: 84%

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

Yoo

Hong

et al. 2020

Antioxidants

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“…Methylglyoxal (MG), a by-product of glycolysis, is present ubiquitously in living cells ( 109 – 111 ). MG induces the production of advanced glycation end products and promotes tumor proliferation in vivo ( 112 , 113 ). Because tumors exhibit high rates of aerobic glycolysis, enhanced aerobic glycolysis in tumors leads to the accumulation of MG in the TME, raising concerns about the role of MG in promoting immune evasion.…”

Section: Tumor Metabolites Promote Tumor Immune Evasionmentioning

confidence: 99%

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Jiang

Hsu

et al. 2020

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.

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“…Recently, we have published our observation that GLO1 is overexpressed in human malignant melanoma, detectable in cell culture models and patient samples [ 16 ]. Numerous studies now support a causative role of GLO1 dysregulation in various malignancies including those of the breast, colon, liver, lung, prostate, skin, stomach, and thyroid, among many others [ 4 , 9 , 11 , 17 , 18 , 19 ]. In addition, GLO1 expression has now been identified as a novel prognostic marker in human gastric cancer patients [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Jandova

Perer

Hua

et al. 2020

Cancers

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Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target.

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Methylglyoxal Acts as a Tumor-Promoting Factor in Anaplastic Thyroid Cancer

Cited by 50 publications

References 57 publications

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

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