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A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells. Exp Mol Med 2020; 52:1730-1743. [PMID: 33046822 PMCID: PMC8080717 DOI: 10.1038/s12276-020-00511-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 08/21/2020] [Accepted: 09/09/2020] [Indexed: 01/01/2023] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARɣ) agonists exert powerful anticancer effects by suppressing tumor growth. In this study, we developed PPZ023 (1-(2-(ethylthio)benzyl)-4-(2-methoxyphenyl)piperazine), a novel PPAR ligand candidate, and investigated the underlying signaling pathways in both non-small-cell lung cancer (NSCLC) and radio-resistant NSCLC cells. To identify whether PPZ023 has anticancer effects in NSCLC and radioresistant NSCLC cells, we performed WST-1, LDH, Western blot, and caspase-3 and -9 activity assays. Furthermore, we isolated exosomes from PPZ023-treated NSCLC cells and studied cell death signaling. PPZ023 reduces cell viability and increases LDH cytotoxicity and caspase-3 activity in NSCLC cells. PPZ023 induces cell death by generating reactive oxygen species (ROS) and triggering mitochondrial cytochrome c release. PPZ023 treatment causes cell death via the PERK–eIF2α–CHOP axis in both NSCLC cell lysates and exosomes, and PERK and CHOP knockdown significantly blocks ER stress-mediated apoptosis by reducing cleaved caspase-3. Interestingly, diphenyleneiodonium (DPI, a Nox inhibitor) inhibits PPZ023-induced cell death via ER stress, and PPARɣ knockdown inhibits PPZ023-induced ROS, ER stress, and cell death. Moreover, PPZ023, in combination with radiation, causes synergic cell death via exosomal ER stress in radioresistant NSCLC cells, indicating that PPZ023/radiation overcomes radioresistance. Taken together, our results suggest that PPZ023 is a powerful anticancer reagent for overcoming radioresistance. A novel small molecule drug candidate known as PPZ023 could be a powerful anti-cancer agent due to its ability to overcome the resistance of tumors to radiation therapy. Sung Hee Hong and colleagues at the Korea Institute of Radiological and Medical Sciences in Seoul, South Korea, investigated the effects of the molecule on lung cancer cells, including cells that that had acquired resistance to radiotherapy. PPZ023 induces the death of cancer cells by binding to a protein in a known signaling pathway, which generates damaging chemicals known as reactive oxygen species. The researchers identified additional molecular details of the anti-cancer activity. They found the radiotherapy resistance of cancer cells is reversed when PPZ023 promotes cell death via a pathway interfering with the folding of newly formed proteins in a cell structure called the endoplasmic reticulum.
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The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation. Life Sci 2019; 219:40-73. [DOI: 10.1016/j.lfs.2018.12.059] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/06/2018] [Accepted: 12/31/2018] [Indexed: 11/21/2022]
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Promising neuroprotective effects of β-caryophyllene against LPS-induced oligodendrocyte toxicity: A mechanistic study. Biochem Pharmacol 2018; 159:154-171. [PMID: 30529211 DOI: 10.1016/j.bcp.2018.12.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 12/04/2018] [Indexed: 01/09/2023]
Abstract
Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS-induced oligodendrocytes toxicity may be chosen as an efficient model to evaluate the role of oligodendrocytes in neuroprotective activities of compounds. β-Caryophyllene (BCP) is a selective type 2 cannabinoid (CB2) receptor agonist. However, the mechanisms underlying the anti-inflammatory effects of BCP are not completely understood. On this basis, we aimed to investigate the protective effects of a wide range of BCP concentrations against LPS-induced toxicity in a proliferative oligodendrocyte cell line (OLN-93) and evaluate the possible correlation between BCP concentration and selective modulation of CB2, Nrf2, sphingomyelinase (SMase) and peroxisome proliferator-activated receptors (PPAR)-γ signaling pathways. We found that LPS significantly increases the levels of reactive oxygen species (ROS), nitric oxide (NO) metabolite and tumor necrosis factor (TNF)-α production while decreases the level of GSH. BCP could prevent LPS-induced cytotoxicity and excessive production of NO, ROS, and TNF-α. Also, we demonstrated that BCP's protective effects against LPS-induced oligodendrocytes toxicity were mediated via the CB2 receptor through different pathways including Nrf2/HO-1/anti-oxidant axis, and PPAR-γ, at low (0.2 and 1 µM), and high (10-50 µM) concentrations, respectively. Additionally, we observed that the addition of SMase inhibitors imipramine (IMP) and fluoxetine (FLX) synergistically increased the protective effects of BCP. Finally, BCP at low concentrations exerted promising protective effects that could be considered for the treatment of neurodegenerative disorders such as MS. However, more studies using other models of neurodegenerative diseases should be undertaken to assess different parameters such as the activity or expression of SMase.
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Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, Klaunig JE, Mehta R, Moorwood K, Sanderson T, Sone H, Vadgama P, Wagemaker G, Ward A, Singh N, Al-Mulla F, Al-Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi AI, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan EP, Brown DG, Bisson WH. The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. Carcinogenesis 2015; 36 Suppl 1:S38-S60. [PMID: 26106143 PMCID: PMC4565610 DOI: 10.1093/carcin/bgv030] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 12/09/2014] [Accepted: 12/15/2014] [Indexed: 01/20/2023] Open
Abstract
The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
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Affiliation(s)
- Wilhelm Engström
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden,
| | - Philippa Darbre
- School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6UB, UK
| | - Staffan Eriksson
- Department of Biochemistry, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Box 575, 75123 Uppsala, Sweden
| | - Linda Gulliver
- Faculty of Medicine, University of Otago, PO Box 913, Dunedin 9050, New Zealand
| | - Tove Hultman
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden, School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6UB, UK
| | - Michalis V Karamouzis
- Department of Biological Chemistry Medical School, Institute of Molecular Medicine and Biomedical Research, University of Athens, Marasli 3, Kolonaki, Athens 10676, Greece
| | - James E Klaunig
- Department of Environmental Health, School of Public Health, Indiana University Bloomington , 1025 E. 7th Street, Suite 111, Bloomington, IN 47405, USA
| | - Rekha Mehta
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, 251 Sir F.G. Banting Driveway, AL # 2202C, Tunney's Pasture, Ottawa, Ontario K1A 0K9, Canada
| | - Kim Moorwood
- Department of Biochemistry and Biology, University of Bath , Claverton Down, Bath BA2 7AY, UK
| | - Thomas Sanderson
- INRS-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, Quebec H7V 1B7, Canada
| | - Hideko Sone
- Environmental Exposure Research Section, Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
| | - Pankaj Vadgama
- IRC in Biomedical Materials, School of Engineering & Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Gerard Wagemaker
- Center for Stem Cell Research and Development, Hacettepe University, Ankara 06100, Turkey
| | - Andrew Ward
- Department of Biochemistry and Biology, University of Bath , Claverton Down, Bath BA2 7AY, UK
| | - Neetu Singh
- Centre for Advanced Research, King George's Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy
| | - Anna Maria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - A Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Jayadev Raju
- Regulatoty Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Roslida A Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Hosni K Salem
- Urology Dept. kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Elizabeth P Ryan
- Department of Environmental and Radiological Sciences, Colorado State University//Colorado School of Public Health, Fort Collins CO 80523-1680, USA and
| | - Dustin G Brown
- Department of Environmental and Radiological Sciences, Colorado State University//Colorado School of Public Health, Fort Collins CO 80523-1680, USA and
| | - William H Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
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Samokhvalov V, Zlobine I, Jamieson KL, Jurasz P, Chen C, Lee KSS, Hammock BD, Seubert JM. PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells. Toxicol Lett 2014; 232:10-20. [PMID: 25300478 DOI: 10.1016/j.toxlet.2014.09.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 09/22/2014] [Accepted: 09/24/2014] [Indexed: 12/28/2022]
Abstract
Docosahexaenoic acid (22:6n3, DHA) is an n-3 polyunsaturated fatty acid (PUFA) known to affect numerous biological functions. While DHA possesses many properties that impact cell survival such as suppressing cell growth and inducing apoptosis, the exact molecular and cellular mechanism(s) remain unknown. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate many cell pathways including cell death. As DHA acts as a ligand to PPARs the aim of this study was to examine the involvement of PPARδ in DHA-mediated cytotoxicity toward H9c2 cells. Treatment with DHA (100μM) resulted in a significant decline in cell viability, cellular metabolic activity and total antioxidant capacity coinciding with increased total proteasome activities and activity of released lactate dehydrogenase (LDH). No changes in reactive oxygen species (ROS) production or accumulation of lipid peroxidation products were observed but DHA promoted apoptotic cell death as detected by flow cytometry, increased caspase-3 activity and decreased phosphorylation of Akt. Importantly, DHA enhanced PPARδ DNA binding activity in H9c2 cells strongly signifying that the cytotoxic effect of DHA might be mediated via PPARδ signaling. Co-treatment with the selective PPARδ antagonist GSK 3787 (1μM) abolished the cytotoxic effects of DHA in H9c2 cells. Cytotoxic effects of DHA were attenuated by co-treatment with myriocin, a selective inhibitor of serine palmitoyl transferase (SPT), preventing de novo ceramide biosynthesis. LC/MS analysis revealed that treatment with DHA resulted in the accumulation of ceramide, which was blocked by GSK 3787. Interestingly, inhibition of cytochrome P450 (CYP) oxidase with MS-PPOH (50μM) abolished DHA-mediated cytotoxicity suggesting downstream metabolites as the active mediators. We further demonstrate that CYP oxidase metabolites of DHA, methyl epoxy docosapentaenoate (EDP methyl esters, 1μM) (mix 1:1:1:1:1:1; 4,5-, 7,8-, 10,11-, 13,14-, 16,17- and 19,20-EDP methyl esters) and 19,20-EDP cause cytotoxicity via activation of PPARδ signaling leading to increased levels of intracellular ceramide. These results illustrate novel pathways for DHA-induced cytotoxicity that suggest an important role for CYP-derived metabolites, EDPs.
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Affiliation(s)
- Victor Samokhvalov
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Igor Zlobine
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Kristi L Jamieson
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Paul Jurasz
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Christopher Chen
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Kin Sing Stephen Lee
- Department of Entomology and Nematology, University of California, Davis, CA, USA; UCD Comprehensive Cancer Center, University of California, Davis, CA, USA
| | - Bruce D Hammock
- Department of Entomology and Nematology, University of California, Davis, CA, USA; UCD Comprehensive Cancer Center, University of California, Davis, CA, USA
| | - John M Seubert
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
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Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase. Mol Cell Neurosci 2014; 59:127-34. [DOI: 10.1016/j.mcn.2014.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 01/25/2014] [Accepted: 01/31/2014] [Indexed: 11/21/2022] Open
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Martins IJ. Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/ojemd.2014.44011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Lodi A, Tiziani S, Khanim FL, Günther UL, Viant MR, Morgan GJ, Bunce CM, Drayson MT. Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from myeloma patients at different stages of disease activity identifies acetylcarnitine as a novel marker of active disease. PLoS One 2013; 8:e56422. [PMID: 23431376 PMCID: PMC3576408 DOI: 10.1371/journal.pone.0056422] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 01/08/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Biomarker identification is becoming increasingly important for the development of personalized or stratified therapies. Metabolomics yields biomarkers indicative of phenotype that can be used to characterize transitions between health and disease, disease progression and therapeutic responses. The desire to reproducibly detect ever greater numbers of metabolites at ever diminishing levels has naturally nurtured advances in best practice for sample procurement, storage and analysis. Reciprocally, since many of the available extensive clinical archives were established prior to the metabolomics era and were not processed in such an 'ideal' fashion, considerable scepticism has arisen as to their value for metabolomic analysis. Here we have challenged that paradigm. METHODS We performed proton nuclear magnetic resonance spectroscopy-based metabolomics on blood serum and urine samples from 32 patients representative of a total cohort of 1970 multiple myeloma patients entered into the United Kingdom Medical Research Council Myeloma IX trial. FINDINGS Using serial paired blood and urine samples we detected metabolite profiles that associated with diagnosis, post-treatment remission and disease progression. These studies identified carnitine and acetylcarnitine as novel potential biomarkers of active disease both at diagnosis and relapse and as a mediator of disease associated pathologies. CONCLUSIONS These findings show that samples conventionally processed and archived can provide useful metabolomic information that has important implications for understanding the biology of myeloma, discovering new therapies and identifying biomarkers potentially useful in deciding the choice and application of therapy.
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Affiliation(s)
- Alessia Lodi
- School of Cancer Sciences, The University of Birmingham, Birmingham, United Kingdom
- Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas, United States of America
| | - Stefano Tiziani
- School of Cancer Sciences, The University of Birmingham, Birmingham, United Kingdom
- Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas, United States of America
- Dell Pediatric Research Institute, The University of Texas at Austin, Austin, Texas, United States of America
| | - Farhat L. Khanim
- School of Biosciences, The University of Birmingham, Birmingham, United Kingdom
| | - Ulrich L. Günther
- School of Cancer Sciences, The University of Birmingham, Birmingham, United Kingdom
| | - Mark R. Viant
- School of Biosciences, The University of Birmingham, Birmingham, United Kingdom
| | - Gareth J. Morgan
- Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | | | - Mark T. Drayson
- School of Immunity and Infection, The University of Birmingham, Birmingham, United Kingdom
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Up-regulation of GADD45alpha expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths. Apoptosis 2010; 14:1341-51. [PMID: 19757064 DOI: 10.1007/s10495-009-0399-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Growth arrest and DNA damage inducible 45 alpha (GADD45alpha) is a central player in mediating apoptosis induced by a variety of stress stimuli and genotoxic agents. Regular usage of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac is associated with reduced risk for various cancers, including colon cancer. The role of GADD45alpha in NSAID-induced colon cancer cell cytotoxicity is unknown. In this study, we report that indomethacin and sulindac sulfide treatments up-regulate GADD45alpha mRNA expression and protein levels in colon cancer HT-29, RKO and Caco-2 cells. This up-regulation of GADD45alpha is accompanied by necrotic cell death and apoptosis. Anti-sense suppression of GADD45alpha expression inhibited indomethacin and sulindac sulfide-induced necrotic cell death and apoptosis. These findings confirm a role for GADD45alpha in NSAID-induced cytotoxicity, a mechanism for the anti-neoplastic effect of NSAIDs in colon tumorigenesis and cancer growth.
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Svircev Z, Baltić V, Gantar M, Juković M, Stojanović D, Baltić M. Molecular aspects of microcystin-induced hepatotoxicity and hepatocarcinogenesis. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2010; 28:39-59. [PMID: 20390967 DOI: 10.1080/10590500903585382] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
It is known that microcystin (MC) is a cyanotoxin that is a potent environmental inhibitor of eucariotic protein serine/threonine phosphatase 1 and 2A, both in vitro and in vivo. Consequently, these cyanobacterial toxins (MC-IARC group 2B carcinogen, MC extracts-group 3) are potent tumor promoters and there is an indication that they may also act as tumor initiators. The ability of microcystin-LR (MC-LR) to act as a tumor initiator is based on fact that it can induce DNA damage either by direct interaction with DNA or by indirect mechanisms through formation of reactive oxygen species (ROS). Both acute and chronic exposures, to either low or high doses of MC-LR, can activate apoptotic pathways. Chronic exposure to low concentrations of MC-LR contributes to increased risk for cancer development. Epidemiological studies, in certain areas of China, have suggested that MC is one of the risk factors for the high incidence of primary liver cancer (PLC). Recently, we have reported a correlation between PLC and cyanobacterial "blooms" in reservoirs used as a source for drinking water supply in central Serbia. It appears that the combination of acute and chronic exposures to both high and low doses of MC can lead to PLC initiation and promotion. Based on this, we propose that the requirement for the co-factors such as aflatoxin B1 and other mycotoxins, HBV, HCV, alcohol, etc. is not needed for initiation and promotion of PLC by MC-LR as was suggested earlier. The possible mechanisms of the genotoxicity of MC and its role as a hepatocarcinogen are outlined in this review. Furthermore, we show that the exposure of hepatocytes to MC can lead either to malignant proliferation or apoptosis.
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Affiliation(s)
- Z Svircev
- Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Serbia.
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Wang J, Lv XW, Du YG. Potential mechanisms involved in ceramide-induced apoptosis in human colon cancer HT29 cells. BIOMEDICAL AND ENVIRONMENTAL SCIENCES : BES 2009; 22:76-85. [PMID: 19462692 DOI: 10.1016/s0895-3988(09)60026-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
OBJECTIVE To investigate the potential mechanisms of cell death after the treatment with ceramide. METHODS MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential mechanisms of cell death after the treatment with C2-ceramide. RESULTS A short-time treatment with C2-ceramide induced cell death, which was associated with p38 MAP kinase activation, but had no links with typical caspase activation or PARP degradation. Rather than caspase inhibitor, Inhibitor of p38 MAP kinase blocked cell death induced by a short-time treatment with ceramide (<12 h). However, inhibition of p38 MAP kinase could not block cell death induced by a prolonged treatment with ceramide (>12 h). Moreover, incubation of cells with ceramide for a long time (>12 h) increased subG1, but reduced S phase accompanied by caspase-dependent and caspase-independent changes including NFkappaB activation. CONCLUSION Ceramide-induced cell apoptosis involves both caspase-dependent and -independent signaling pathway. Caspase-independent cell death occurring in a relatively early stage, which is mediated via p38 MAP kinase, can progress into a stage involving both caspase-dependent and -independent mechanisms accompanied by cell signaling of MAPKs and NFkappaB.
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Affiliation(s)
- Jing Wang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
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Wang J, Lv XW, Shi JP, Hu XS. Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells. World J Gastroenterol 2007; 13:1129-34. [PMID: 17373752 PMCID: PMC4146880 DOI: 10.3748/wjg.v13.i7.1129] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells. Possible molecular mechanisms were explored.
METHODS: [3- (4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, plasmid transfection, reporter assay, FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells.
RESULTS: C2-ceramide was found to inhibit the growth of Bel7402 cells by inducing cell cycle arrest. During the process, the expression of p21 protein increased, while that of cyclinD1, phospho-ERK1/2 and c-myc decreased. Furthermore, the level of CDK7 was downregulated, while the transcriptional activity of PPARγ was upregulated. Addition of GW9662, which is a PPARγ specific antagonist, could reserve the modulation action on CDK7.
CONCLUSION: Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7, at least partly, through PPARγ activation. The ERK signaling pathway was involved in this process.
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Affiliation(s)
- Jing Wang
- Research Center for Eco-Environmental Sciences, The Chinese Academy of Sciences, Haidian District, Beijing 100085, China.
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