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Neurochemistry International Jan 2020Thioredoxin interacting protein (TXNIP) binds to thioredoxin thereby limiting its activity, but it also promotes internalization of glucose transporters, participates in...
Thioredoxin interacting protein (TXNIP) binds to thioredoxin thereby limiting its activity, but it also promotes internalization of glucose transporters, participates in inflammasome activation, and controls autophagy. Published data and this work demonstrate that TXNIP responds to a number of apparently unrelated stresses, such as serum deprivation, pH change, and oxidative, osmotic and carbonyl stress. Interestingly, we noticed that hyperosmotic (NaCl) and carbonyl (methylglyoxal, MGO) stresses in HT22 neuronal cells produced a rapid loss of TXNIP (half-life ∼12 min), prompting us to search for possible mechanisms controlling this TXNIP loss, including pH change, serum deprivation, calcium metabolism and inhibition of the proteasome and other proteases, autophagy and MAPKs. None of these routes stopped the TXNIP loss induced by hyperosmotic and carbonyl stress. Besides transcriptional, translational and microRNA regulation, there is evidence indicating that mTOR and AMPK also control TXNIP expression. Indeed, AMPK-deficient mouse embryonic fibroblasts failed to respond to phenformin (AMPK activator) and compound C (AMPK inhibitor), while rapamycin induced a marked increase in TXNIP levels, confirming the known AMPK/mTOR control over TXNIP. However, the TXNIP loss induced by NaCl or MGO were observed even in AMPK deficient MEFs or after mTOR inhibition, indicating AMPK/mTOR does not participate in this rapid TXNIP loss. These results suggest that rapid TXNIP loss is a general and immediate response to stress that can improve energy availability and antioxidant protection, eventually culminating in better cell survival.
Topics: Animals; Carbon; Carrier Proteins; Cell Line, Transformed; Mice; Neurons; Osmotic Pressure; Oxidative Stress; RNA, Small Interfering; Thioredoxins; Time Factors
PubMed: 31678323
DOI: 10.1016/j.neuint.2019.104585 -
Oxidative Medicine and Cellular... 2021Nephrotoxicity is a common complication of cisplatin chemotherapy and, thus, limits the clinical application of cisplatin. In this work, the effects of catalpol (CAT), a...
Nephrotoxicity is a common complication of cisplatin chemotherapy and, thus, limits the clinical application of cisplatin. In this work, the effects of catalpol (CAT), a bioactive ingredient extracted from Rehmannia glutinosa, on cisplatin-induced nephrotoxicity and antitumor efficacy were comprehensively investigated. Specifically, the protective effect of CAT on cisplatin-induced injury was explored in mice and HK-2 cells. , CAT administration strikingly suppressed cisplatin-induced renal dysfunction, morphology damage, apoptosis, and inflammation. , CAT induced activation of adenosine 5'-monophosphate- (AMP-) activated protein kinase (AMPK), improved mitochondrial function, and decreased generation of cellular reactive oxygen species (ROS), leading to a reduction in inflammation and apoptosis, which ultimately protected from cisplatin-induced injury. However, the beneficial effects of CAT were mostly blocked by coincubation with compound C. Furthermore, molecular docking results indicated that CAT had a higher affinity for AMPK than other AMPK activators such as danthron, phenformin, and metformin. Importantly, CAT possessed the ability to reverse drug resistance without compromising the antitumor properties of cisplatin. These findings suggest that CAT exerts positive effects against cisplatin-induced renal injury through reversing drug resistance via the mitochondrial-dependent pathway without affecting the anticancer activity of cisplatin.
Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Cisplatin; Enzyme Activation; Iridoid Glucosides; Kidney Diseases; Male; Mice; Mitochondria
PubMed: 33510841
DOI: 10.1155/2021/7467156 -
Scientific Reports May 2020One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed for increased proliferation. Although inhibitors of this...
One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed for increased proliferation. Although inhibitors of this pathway are widely used to treat many cancers, their global impact on anabolic and catabolic processes remains unclear. Using a combination of real-time bioenergetics assays and metabolomics approaches, we investigated the global effects of methotrexate on cellular metabolism. We show that methotrexate treatment increases the intracellular concentration of the metabolite AICAR, resulting in AMPK activation. Methotrexate-induced AMPK activation leads to decreased one-carbon metabolism gene expression and cellular proliferation as well as increased global bioenergetic capacity. The anti-proliferative and pro-respiratory effects of methotrexate are AMPK-dependent, as cells with reduced AMPK activity are less affected by methotrexate treatment. Conversely, the combination of methotrexate with the AMPK activator, phenformin, potentiates its anti-proliferative activity in cancer cells. These data highlight a reciprocal effect of methotrexate on anabolic and catabolic processes and implicate AMPK activation as a metabolic determinant of methotrexate response.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Biguanides; Cell Line, Tumor; Cell Proliferation; Cell Respiration; Drug Synergism; Humans; Methotrexate; Mitochondria; Signal Transduction
PubMed: 32398698
DOI: 10.1038/s41598-020-64460-z -
Hereditas Apr 2021Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and...
BACKGROUND
Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and progression in T2DM remain unclear.
METHODS
The microarray data from Gene Expression Omnibus (GEO) were analyzed to screen differentially expressed genes (DEGs) of T2DM and HCC dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed on these DEGs to detect the modules and genes, respectively. Common genes in modules with clinical interests of T2DM and HCC were obtained and annotated via GOSemSim package and Metascape. Genes related to late-stage HCC and high glycated haemoglobin (HbA1c) were also identified. These genes were validated by UALCAN analysis and univariate cox regression based on The Cancer Genome Atlas (TCGA). Finally, another two independent datasets were applied to confirm the results of our study.
RESULTS
A total of 1288 and 1559 DEGs of T2DM and HCC were screened, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed several shared pathways in two diseases, such as pathways in cancer and metabolism. A total of 37 common genes correlated with T2DM and HCC were then identified with WGCNA. Furthermore, 12 genes from modules associated with late-stage HCC and high HbA1c were regarded as hub genes. Among these genes, 8 genes associated with tumor invasion and metastasis were validated by UALCAN analysis. Moreover, downregulations of ACAT1, SLC2A2, PCK1 and ABAT were significantly associated with poorer prognosis in HCC patients with elevated HbA1c. Additionally, the expressions of PCK1 and ABAT were raised in HepG2 cells pre-treated with metformin and phenformin.
CONCLUSIONS
The present study confirmed several metabolic genes related to hyperglycemia and malignant tumor, which may provide not only new insights into the pathogenesis of hepatocarcinogenesis and progression in T2DM, but also novel therapeutic targets for T2DM patients with HCC in the future.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Gene Ontology; Glycated Hemoglobin; Hep G2 Cells; Humans; Liver Neoplasms; Oligonucleotide Array Sequence Analysis; Risk Factors
PubMed: 33865459
DOI: 10.1186/s41065-021-00177-x -
Cell Reports Dec 2019Metabolic flexibility allows cells to adapt to various environments and limits the efficacy of metabolic drugs. Therapeutic targeting of cancer metabolism relies on...
Metabolic flexibility allows cells to adapt to various environments and limits the efficacy of metabolic drugs. Therapeutic targeting of cancer metabolism relies on defining limiting requirements and vulnerabilities in the highly dynamic metabolic network. Here, we characterize the metabolic reprogramming and identify cancer-specific metabolic vulnerabilities in response to the pharmacological inhibition of mitochondrial complex I. Our work reveals the adaptation mechanism in malignant lymphocytes providing resistance against the biguanides phenformin and metformin by transcriptionally reprogramming glucose metabolism. Metabolic adaptation to complex I inhibition is mediated by mitochondrial reactive oxygen species (mROS) serving as a mitochondrial stress signal activating hypoxia-inducible factor-1a (HIF-1a). Inhibition of the mROS/HIF-1a axis through antioxidants or direct suppression of HIF-1a selectively disrupts metabolic adaptation and survival during complex I dysfunction in malignant lymphocytes. Our results identify HIF-1a signaling as a critical factor in resistance against biguanide-induced mitochondrial dysfunction, allowing selective targeting of metabolic pathways in leukemia and lymphoma.
Topics: Adolescent; Adult; Aged; Animals; Carbohydrate Metabolism; Cell Hypoxia; Cell Line; Cell Line, Tumor; Electron Transport Complex I; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Jurkat Cells; Lymphocytes; Male; Metformin; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mitochondria; Reactive Oxygen Species; Signal Transduction; Young Adult
PubMed: 31801069
DOI: 10.1016/j.celrep.2019.11.007 -
Theranostics 2021The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic...
The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic ductal adenocarcinoma (PDAC). knockdown significantly reduced tumor formation in PDAC. We raised a question how ALDH7A1 contributes to cancer progression. To answer the question, the role of ALDH7A1 in energy metabolism was investigated by knocking down and knockdown gene in mouse model, because the role of ALDH7A1 has been reported as a catabolic enzyme catalyzing fatty aldehyde from lipid peroxidation to fatty acid. Oxygen consumption rate (OCR), ATP production, mitochondrial membrane potential, proliferation assay and immunoblotting were performed. In study, two human PDAC cell lines were used for pre-clinical xenograft model as well as spontaneous PDAC model of KPC mice was also employed for anti-cancer therapeutic effect. knockdown significantly reduced tumor formation with reduction of OCR and ATP production, which was inversely correlated with increase of 4-hydroxynonenal. This implies that ALDH7A1 is critical to process fatty aldehydes from lipid peroxidation. Overall survival of PDAC is doubled by cross breeding of KPC () and mice. Inhibitions of ALDH7A1 and oxidative phosphorylation using gossypol and phenformin resulted in a regression of tumor formation in xenograft mice model and KPC mice model.
Topics: Aldehyde Dehydrogenase; Aldehydes; Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Gossypol; Homeodomain Proteins; Humans; Lipid Peroxidation; Mice; Mice, Knockout; Mice, Nude; Oxidative Phosphorylation; Pancreatic Neoplasms; Phenformin; Proto-Oncogene Proteins p21(ras); Signal Transduction; Survival Analysis; Trans-Activators; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 33537098
DOI: 10.7150/thno.53935 -
Cell Reports. Medicine May 2020Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling...
Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated expression in lymphoma cells promotes increased apoptosis to biguanide treatment and . This effect is driven by the -dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between expression and biguanide sensitivity in human cancer cells. Our results identify expression as a potential biomarker for biguanide sensitivity in malignancies.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Apoptosis; Biguanides; Drug Resistance, Neoplasm; Drug Synergism; HEK293 Cells; Humans; Lymphoma; Mice; Mice, Nude; Proto-Oncogene Proteins c-myc; RNA, Long Noncoding; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32478334
DOI: 10.1016/j.xcrm.2020.100014 -
Nature Communications Jun 2021Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to...
Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Electron Transport Complex I; Energy Metabolism; Female; Glutathione; Humans; Interferon-gamma; MCF-7 Cells; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Oxidative Stress; Phenformin; Poly I-C; Reactive Oxygen Species; STAT1 Transcription Factor; Xenograft Model Antitumor Assays
PubMed: 34083537
DOI: 10.1038/s41467-021-23396-2 -
IScience Feb 2024Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut...
Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (K) of agmatinase is 1 mM and relevant in the gut where the drug concentration is 1-10 mM. Metformin analogs phenformin, buformin, and galegine are even more potent inhibitors of agmatinase (K = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin's therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin's action in the gut and may lead to significant discoveries in improving metformin therapy.
PubMed: 38318350
DOI: 10.1016/j.isci.2024.108900 -
Scientific Reports Nov 2019The major source of ATP in cancer cells remains unclear. Here, we examined energy metabolism in gastric cancer cells and found increased fatty acid oxidation and...
The major source of ATP in cancer cells remains unclear. Here, we examined energy metabolism in gastric cancer cells and found increased fatty acid oxidation and increased expression of ALDH3A1. Metabolic analysis showed that lipid peroxidation by reactive oxygen species led to spontaneous production of 4-hydroxynonenal, which was converted to fatty acids with NADH production by ALDH3A1, resulting in further fatty acid oxidation. Inhibition of ALDH3A1 by knock down using siRNA of ALDH3A1 resulted in significantly reduced ATP production by cancer cells, leading to apoptosis. Oxidative phosphorylation by mitochondria in gastric cancer cells was driven by NADH supplied via fatty acid oxidation. Therefore, blockade of ALDH3A1 together with mitochondrial complex I using gossypol and phenformin led to significant therapeutic effects in a preclinical gastric cancer model.
Topics: Adenosine Triphosphate; Aldehyde Dehydrogenase; Animals; Cell Line, Tumor; Cell Proliferation; Fatty Acids; Female; Gene Knockdown Techniques; Gossypol; Humans; Male; Mice; Oxidation-Reduction; Phenformin; Stomach Neoplasms
PubMed: 31705020
DOI: 10.1038/s41598-019-52814-1