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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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2
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Dixit G, Prabhu A. The pleiotropic peroxisome proliferator activated receptors: Regulation and therapeutics. Exp Mol Pathol 2021; 124:104723. [PMID: 34822814 DOI: 10.1016/j.yexmp.2021.104723] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential. This article is an attempt to present a rational analysis of the multifaceted therapeutic effects and underlying mechanisms of isotype-specific PPAR agonists, dual PPAR agonists, pan PPAR agonists as well as PPAR antagonists. A holistic understanding of the mechanistic dimensions of these key metabolic regulators will guide future efforts to identify novel molecules in the realm of metabolic, inflammatory and immunotherapeutic diseases.
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Affiliation(s)
- Gargi Dixit
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Arati Prabhu
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
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3
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Mikulčić M, Tabrizi-Wizsy NG, Bernhart EM, Asslaber M, Trummer C, Windischhofer W, Sattler W, Malle E, Hrzenjak A. 15d-PGJ 2 Promotes ROS-Dependent Activation of MAPK-Induced Early Apoptosis in Osteosarcoma Cell In Vitro and in an Ex Ovo CAM Assay. Int J Mol Sci 2021; 22:ijms222111760. [PMID: 34769194 PMCID: PMC8583949 DOI: 10.3390/ijms222111760] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma (OS) is the most common type of bone tumor, and has limited therapy options. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has striking anti-tumor effects in various tumors. Here, we investigated molecular mechanisms that mediate anti-tumor effects of 15d-PGJ2 in different OS cell lines. Human U2-OS and Saos-2 cells were treated with 15d-PGJ2 and cell survival was measured by MTT assay. Cell proliferation and motility were investigated by scratch assay, the tumorigenic capacity by colony forming assay. Intracellular ROS was estimated by H2DCFDA. Activation of MAPKs and cytoprotective proteins was detected by immunoblotting. Apoptosis was detected by immunoblotting and Annexin V/PI staining. The ex ovo CAM model was used to study growth capability of grafted 15d-PGJ2-treated OS cells, followed by immunohistochemistry with hematoxylin/eosin and Ki-67. 15d-PGJ2 substantially decreased cell viability, colony formation and wound closure capability of OS cells. Non-malignant human osteoblast was less affected by 15d-PGJ2. 15d-PGJ2 induced rapid intracellular ROS production and time-dependent activation of MAPKs (pERK1/2, pJNK and pp38). Tempol efficiently inhibited 15d-PGJ2-induced ERK1/2 activation, while N-acetylcystein and pyrrolidine dithiocarbamate were less effective. Early but weak activation of cytoprotective proteins was overrun by induction of apoptosis. A structural analogue, 9,10-dihydro-15d-PGJ2, did not show toxic effects in OS cells. In the CAM model, we grafted OS tumors with U2-OS, Saos-2 and MG-63 cells. 15d-PGJ2 treatment resulted in significant growth inhibition, diminished tumor tissue density, and reduced tumor cell proliferation for all cell lines. Our in vitro and CAM data suggest 15d-PGJ2 as a promising natural compound to interfere with OS tumor growth.
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Affiliation(s)
- Mateja Mikulčić
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria;
| | - Nassim Ghaffari Tabrizi-Wizsy
- Otto Loewi Research Center, Division of Immunology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria;
| | - Eva M. Bernhart
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (E.M.B.); (C.T.); (W.S.); (E.M.)
| | - Martin Asslaber
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria;
| | - Christopher Trummer
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (E.M.B.); (C.T.); (W.S.); (E.M.)
- Department of Pediatrics and Adolescence Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Werner Windischhofer
- Department of Pediatrics and Adolescence Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Wolfgang Sattler
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (E.M.B.); (C.T.); (W.S.); (E.M.)
| | - Ernst Malle
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (E.M.B.); (C.T.); (W.S.); (E.M.)
| | - Andelko Hrzenjak
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria;
- Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, 8010 Graz, Austria
- Correspondence: ; Tel.: +43-316-385-73860
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4
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Kim SJ, Cho NC, Han B, Kim K, Hahn YI, Kim KP, Suh YG, Choi BY, Na HK, Surh YJ. 15-Deoxy-Δ 12,14 -prostaglandin J 2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H-Ras-transformed human breast epithelial cells. FEBS Lett 2021; 595:604-622. [PMID: 33452674 DOI: 10.1002/1873-3468.14040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 01/02/2023]
Abstract
Signal transducer and activator of transcription 3 (STAT3) has been considered as a potential target for development of anticancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin, 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) functions as an allosteric inhibitor of STAT3. 15d-PGJ2 inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H-Ras-transformed human mammary epithelial cells (MCF10A-Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d-PGJ2 analogues reveal that both C12-C13 and C9-C10 double bonds conjugated to the carbonyl group in the cyclopentenone ring of 15d-PGJ2 are essential for STAT3 binding. Antiproliferative and pro-apoptotic activities of 15d-PGJ2 in MCF10A-Ras cells are attributable to covalent modification of STAT3 on Cys259, and mimic the effects induced by mutation of this amino acid.
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Affiliation(s)
- Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea
| | - Nam-Chul Cho
- Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Korea
| | - Bitnara Han
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Korea
| | - Kyeojin Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea
| | - Young-Il Hahn
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Korea.,Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Korea
| | - Young Ger Suh
- College of Pharmacy, CHA University, Gyeonggi-do, Korea
| | - Bu Young Choi
- Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Chungbuk, Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge Based Services Engineering, Sungshin Women's University, Seoul, Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.,Cancer Research Institute, Seoul National University, Korea
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5
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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Iuchi K, Ema M, Suzuki M, Yokoyama C, Hisatomi H. Oxidized unsaturated fatty acids induce apoptotic cell death in cultured cells. Mol Med Rep 2019; 19:2767-2773. [PMID: 30720142 PMCID: PMC6423586 DOI: 10.3892/mmr.2019.9940] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 01/28/2019] [Indexed: 12/20/2022] Open
Abstract
Polyunsaturated fatty acids are oxidized by non-enzymatic or enzymatic reactions. The oxidized products are multifunctional. In this study, we investigated how oxidized fatty acids inhibit cell proliferation in cultured cells. We used polyunsaturated and saturated fatty acids, docosahexaenoic acid (DHA; 22:6), eicosapentaenoic acid (EPA; 20:5), linoleic acid (LA; 18:2), and palmitic acid (16:0). Oxidized fatty acids were produced by autoxidation of fatty acids for 2 days in the presence of a gas mixture (20% O2 and 80% N2). We found that oxidized polyunsaturated fatty acids (OxDHA, OxEPA and OxLA) inhibited cell proliferation much more effectively compared with un-oxidized fatty acids (DHA, EPA and LA, respectively) in THP-1 (a human monocytic leukemia cell line) and DLD-1 (a human colorectal cancer cell line) cells. In particular, OxDHA markedly inhibited cell proliferation. DHA has the largest number of double bonds and is most susceptible to oxidation among the fatty acids. OxDHA has the largest number of highly active oxidized products. Therefore, the oxidative levels of fatty acids are associated with the anti-proliferative activity. Moreover, caspase-3/7 was activated in the cells treated with OxDHA, but not in those treated with DHA. A pan-caspase inhibitor (zVAD-fmk) reduced the cell death induced by OxDHA. These results indicated that oxidized products from polyunsaturated fatty acids induced apoptosis in cultured cells. Collectively, the switch between cell survival and cell death may be regulated by the activity and/or number of oxidized products from polyunsaturated fatty acids.
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Affiliation(s)
- Katsuya Iuchi
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180‑8633, Japan
| | - Mika Ema
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180‑8633, Japan
| | - Moe Suzuki
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180‑8633, Japan
| | - Chikako Yokoyama
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992‑8510, Japan
| | - Hisashi Hisatomi
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180‑8633, Japan
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Diabetes Mellitus and Risk of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5202684. [PMID: 29379799 PMCID: PMC5742888 DOI: 10.1155/2017/5202684] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is two to three times higher in patients with diabetes mellitus (DM), the prevalence of which is increasing sharply worldwide. The purpose of this review was to describe clinical links between DM and HCC and potential biological mechanisms that may account for this association. We evaluated the role of potential pathways that could account for the development of HCC with different etiologies in the presence of DM. In addition, we also briefly discuss the potential effect of other factors such as type and dosage of antidiabetic medicines and duration of DM on HCC risk.
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Yamamoto Y, Yamamoto T, Koma H, Nishii A, Yagami T. Synergistic effects of 15-deoxy Δ 12,14-prostaglandin J 2 on the anti-tumor activity of doxorubicin in renal cell carcinoma. Biochem Biophys Rep 2017; 9:61-66. [PMID: 28955990 PMCID: PMC5614541 DOI: 10.1016/j.bbrep.2016.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 11/04/2016] [Accepted: 11/08/2016] [Indexed: 12/24/2022] Open
Abstract
An endogenous anticancer agent, 15-deoxy -Δ12,14-prostaglandin J2 (15d-PGJ2) induces apoptosis in the chemoresistant renal cell carcinoma (RCC). Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor for 15d-PGJ2, and mediates the cytotoxicity of 15d-PGJ2 in many cancerous cells. However, 15d-PGJ2 induces apoptosis independently of PPARγ in human RCC cell line such as Caki-2. In the present study, we found that 15d-PGJ2 ameliorated the chemoresistance to one of anthracycline antibiotics, doxorubicin, in Caki-2 cells. Doxorubicin alone exhibited weak cytotoxicity at the concentrations effective for other cancer cells such as Hela cells. In addition, it did not activate caspase 3. However, the cytotoxicity of doxorubicin was increased remarkably and accompanied with the caspase- 3 activation in the presence of 15d-PGJ2. Doxorubicin alone damaged plasma membrane, and the combined application of 15d-PGJ2 with doxorubicin increased the membrane permeability slightly. PPARγ was involved in neither the anti-tumor activity nor the synergistic effect of 15d-PGJ2. 15d-PGJ2 induces apoptosis in Caki-2 cells via suppressing the phosphoinositide 3-kinase (PI3K)-Akt pathway. The effect of PI3K inhibitor on the cytotoxicity of doxorubicin was additive, but not synergistic. Although the PI3K inhibitor mimicked the cytotoxicity of 15d-PGJ2, it might not be involved in the synergism between 15d-PGJ2 and doxorubicin. In conclusion, 15d-PGJ2 enhanced the chemosensitivity of doxorubicin via the pathway independent of PPARγ and PI3K.
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Affiliation(s)
- Yasuhiro Yamamoto
- Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan
| | - Takehiro Yamamoto
- Hyogo Prefectural Kobe High School, 1-5-1 Shironoshita-dori, Nada-ku, Kobe, Hyogo 657-0804, Japan
| | - Hiromi Koma
- Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan
| | - Ayaka Nishii
- Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan
| | - Tatsurou Yagami
- Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan
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9
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Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2. PLoS One 2016; 11:e0147390. [PMID: 26820738 PMCID: PMC4731085 DOI: 10.1371/journal.pone.0147390] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 01/04/2016] [Indexed: 01/17/2023] Open
Abstract
Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.
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Pon CK, Firth SM, Baxter RC. Involvement of insulin-like growth factor binding protein-3 in peroxisome proliferator-activated receptor gamma-mediated inhibition of breast cancer cell growth. Mol Cell Endocrinol 2015; 399:354-61. [PMID: 25449421 DOI: 10.1016/j.mce.2014.10.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 10/24/2014] [Accepted: 10/28/2014] [Indexed: 12/19/2022]
Abstract
We have previously reported that insulin-like growth factor binding protein-3 (IGFBP-3), a protein with dichotomous effects on both cell proliferation and cell survival, interacts with peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits adipogenic PPARγ signaling. We now show that IGFBP-3 and PPARγ interact in breast cancer cells, through amino- and carboxyl-terminal residues of IGFBP-3. IGFBP-3 and the PPARγ ligands, rosiglitazone or 15-deoxy-Δ(12,14)-prostaglandin J2, separately inhibited the proliferation of MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells. However, growth inhibition by IGFBP-3 and PPARγ ligand combined was greater than by either alone. Two IGFBP-3 mutants with reduced PPARγ binding caused no growth inhibition when used alone and abolished the inhibitory effect of rosiglitazone when used in combination with PPARγ ligand. Cell growth inhibition by PPARγ ligands was substantially blocked by IGFBP-3 siRNA and restored by exogenous IGFBP-3. We conclude that the interaction between IGFBP-3 and PPARγ is important for the growth-inhibitory effect of PPARγ ligands in human breast cancer cells, suggesting that IGFBP-3 expression by breast tumors may regulate their sensitivity toward PPARγ ligands.
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Affiliation(s)
- Cindy K Pon
- Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Sue M Firth
- Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Robert C Baxter
- Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
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Hydroxyoctadecadienoic Acids Regulate Apoptosis in Human THP-1 Cells in a PPARγ-Dependent Manner. Lipids 2014; 49:1181-92. [DOI: 10.1007/s11745-014-3954-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 09/11/2014] [Indexed: 12/13/2022]
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12
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Yaacob NS, Nasir R, Norazmi MN. Influence of 17β-estradiol on 15-deoxy-δ12,14 prostaglandin J2 -induced apoptosis in MCF-7 and MDA-MB-231 cells. Asian Pac J Cancer Prev 2014; 14:6761-7. [PMID: 24377602 DOI: 10.7314/apjcp.2013.14.11.6761] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of PPARγ, 15-deoxy-Δ12,14 prostaglandin J2 (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha (ERα)-positive (MCF-7) and ERα-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between PPARγ and ERα, the effect of the ERα ligand, 17β-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The PPARγ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances PPARγ-independent anticancer effects of PGJ2 in the presence of its receptor.
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Affiliation(s)
- Nik Soriani Yaacob
- Department of Chemical Pathology, Universiti Sains Malaysia, Health Campus, Kelantan, Malaysia E-mail :
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13
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Synergistic Antiproliferative Effects of Combined γ -Tocotrienol and PPAR γ Antagonist Treatment Are Mediated through PPAR γ -Independent Mechanisms in Breast Cancer Cells. PPAR Res 2014; 2014:439146. [PMID: 24729783 PMCID: PMC3960771 DOI: 10.1155/2014/439146] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 01/23/2014] [Indexed: 01/16/2023] Open
Abstract
Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis.
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14
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Emerging roles of peroxisome proliferator-activated receptor gamma in cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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15
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Colin-Cassin C, Yao X, Cerella C, Chbicheb S, Kuntz S, Mazerbourg S, Boisbrun M, Chapleur Y, Diederich M, Flament S, Grillier-Vuissoz I. PPARγ-inactive Δ2-troglitazone independently triggers ER stress and apoptosis in breast cancer cells. Mol Carcinog 2013; 54:393-404. [PMID: 24293218 DOI: 10.1002/mc.22109] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 10/08/2013] [Accepted: 10/23/2013] [Indexed: 01/02/2023]
Abstract
Our aim was to better understand peroxisome proliferator-activated receptor gamma (PPARγ)-independent pathways involved in anti-cancer effects of thiazolidinediones (TZDs). We focused on Δ2-troglitazone (Δ2-TGZ), a PPARγ inactive TZD that affects breast cancer cell viability. Appearance of TUNEL positive cells, changes in mitochondrial membrane potential, cleavage of poly(ADP-ribose) polymerase (PARP)-1 and caspase-7 revealed that apoptosis occurred in both hormone-dependent MCF7 and hormone-independent MDA-MB-231 breast cancer cells after 24 and 48 h of treatment. A microarray study identified endoplasmic reticulum (ER) stress as an essential cellular function since many genes involved in ER stress were upregulated in MCF7 cells following Δ2-TGZ treatment. Δ2-TGZ-induced ER stress was further confirmed in MCF7 cells by phosphorylation of pancreatic endoplasmic reticulum kinase-like endoplasmic reticulum kinase (PERK) and its target eIF2α after 1.5 h, rapid increase in activating transcription factor (ATF) 3 mRNA levels, splicing of X-box binding protein 1 (XBP1) after 3 h, accumulation of binding immunogloblulin protein (BiP) and CCAAT-enhancer-binding protein homologous protein (CHOP) after 6 h. Immunofluorescence microscopy indicated that CHOP was relocalized to the nucleus of treated cells. Similarly, in MDA-MB-231 cells, overexpression of ATF3, splicing of XBP1, and accumulation of BiP and CHOP were observed following Δ2-TGZ treatment. In MCF7 cells, knock-down of CHOP or the inhibition of c-Jun N-terminal kinase (JNK) did not impair cleavage of PARP-1 and caspase-7. Altogether, our results show that ER stress is an early response of major types of breast cancer cells to Δ2-TGZ, prior to, but not causative of apoptosis.
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Affiliation(s)
- Christelle Colin-Cassin
- Université de Lorraine, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France; CNRS, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France
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Seabrook JL, Cantlon JD, Cooney AJ, McWhorter EE, Fromme BA, Bouma GJ, Anthony RV, Winger QA. Role of LIN28A in mouse and human trophoblast cell differentiation. Biol Reprod 2013; 89:95. [PMID: 24006280 DOI: 10.1095/biolreprod.113.109868] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Proper regulation of trophoblast proliferation, differentiation, and function are critical for placenta development and function. The RNA-binding protein, LIN28A, has been well characterized as a potent regulator of differentiation in embryonic stem cells; however, little is known about the function of LIN28A in the placenta. We assessed LIN28A in vitro using mouse trophoblast stem (mTS) cells and human trophoblast cells (ACH-3P). We observed that LIN28A decreased and let-7 miRNA increased when mTS cells were induced to differentiate into mouse trophoblast giant cells (mTGCs) upon the removal of FGF4, heparin and conditioned medium. Similarly, we observed that LIN28A decreased in ACH-3P cells induced to syncytialize with forskolin treatment. To assess LIN28A in vivo we examined Embryonic Day 11.5 mouse placenta and observed abundant LIN28A in the chorioallantoic interface and labyrinth layer, with little LIN28A staining in spongiotrophoblast or differentiated mTGCs. Additionally, shRNA-mediated LIN28A knockdown in ACH-3P cells resulted in increased spontaneous syncytialization, and increased levels of syncytiotrophoblast markers hCG, LGALS13, and ERVW-1 mRNA. Additionally, targeted degradation of LIN28A mRNA increased responsiveness to forskolin-induced differentiation. In contrast, targeted degradation of Lin28a mRNA in mTS cells did not alter cell phenotype when maintained under proliferative culture conditions. Together, these data establish that LIN28A has a functional role in regulating trophoblast differentiation and function, and that loss of LIN28A in human trophoblast is sufficient to induce differentiation, but does not induce differentiation in the mouse.
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Affiliation(s)
- Jill L Seabrook
- Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado
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Tumor apoptosis in prostate cancer by PGD(2) and its metabolite 15d-PGJ(2) in murine model. Biomed Pharmacother 2012. [PMID: 23206752 DOI: 10.1016/j.biopha.2012.10.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Fifteen-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) is one of non-enzymatically converted metabolite from prostaglandin D(2) (PGD(2)). Anti-tumor effects of 15d-PGJ(2) in various tumors are partially known, but the detail of in vivo mechanisms of action is still unclear. In this study, we investigated the effects of 15d-PGJ(2) and PGD(2) on murine prostate cancer in vitro and in vivo. Murine prostate cancer cells RM9 were transfected with murine prostaglandin D(2) synthase (mPGDS) gene by using defective retrovirus vector, designated as RM9-mPGDS. In addition, RM9 was also transfected with only defective retrovirus vector, designated as RM9-EV and used as control in this study. The expression and production of the gene were confirmed by RT-PCR and ELISA, respectively. For in vivo study, RM9-mPGDS was injected into the back of C57BL/6 mice, then resulted tumor was used for pathological analysis 14days after the inoculation. Tumor cell apoptosis in the tissue was detected by TUNEL staining. Retrovirally transfected mPGDS in RM9 significantly induced apoptosis in vivo but not in vitro, by TUNEL staining and cell death ELISA, respectively. Our results strongly suggested that the apoptosis induced in RM9-mPGDS in vivo was probably achieved in tumor environment such as hypoxic condition. The introduction of PGDS gene into cancer cells might be a novel therapy against cancer.
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Fujita M, Tohji C, Honda Y, Yamamoto Y, Nakamura T, Yagami T, Yamamori M, Okamura N. Cytotoxicity of 15-deoxy-Δ(12,14)-prostaglandin J(2) through PPARγ-independent pathway and the involvement of the JNK and Akt pathway in renal cell carcinoma. Int J Med Sci 2012; 9:555-66. [PMID: 22991494 PMCID: PMC3444976 DOI: 10.7150/ijms.4455] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Accepted: 08/31/2012] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity and action mechanisms of 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of endogenous ligands for PPARγ, in terms of PPARγ-dependency and the mitogen-activated protein kinase (MAPK) and Akt pathway in three human renal cell carcinoma (RCC)-derived cell lines. METHODS 786-O, Caki-2 and ACHN cells were used as human RCC-derived cell lines. Cell viability and caspase-3 activity was detected by fluorescent reagents, and chromatin-condensation was observed with a brightfield fluorescent microscope after staining cells with Hoechst33342. The expression levels of proteins were detected by Western blot analysis. RESULTS 15d-PGJ(2) showed cytotoxicity in dose-dependent manner. 15d-PGJ(2) induced chromatin-condensation and elevated caspase-3 activity, and the cell viability was restored by co-treatment with a pan-caspase inhibitor, Z-VAD-FMK, indicating the involvement of caspase-dependent apoptosis. The cytotoxicity was not impaired by a PPARγ inhibitor, GW9662, suggesting that 15d-PGJ(2) exerted the cytotoxicity in a PPARγ-independent manner. Some antioxidants rescued cells from cell death induced by 15d-PGJ(2), but some did not, suggesting that reactive oxygen species (ROS) did not contribute to the apoptosis. 15d-PGJ(2) also increased the expression levels of phospho-c-Jun N terminal kinase (JNK) in Caki-2 cells, and decreased those of phospho-Akt in 786-O cells, indicating that the JNK MAPK and the Akt pathways participated in the anticancer effects of 15d-PGJ(2) in some cell lines. CONCLUSION 15d-PGJ(2) exerted cytotoxic effects accompanying caspase-dependent apoptosis, and this effect was elicited in a PPARγ-independent manner in three cell lines. In addition, the JNK MAPK and Akt pathway was involved in the cytotoxicity of 15d-PGJ(2) to some extent in some cell line. Therefore, our study showed the 15d-PGJ(2) to potentially be an interesting approach for RCC treatment.
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Affiliation(s)
- Megumi Fujita
- Department of Clinical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien-kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan
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Cytotoxicity of troglitazone through PPARγ-independent pathway and p38 MAPK pathway in renal cell carcinoma. Cancer Lett 2011; 312:219-27. [PMID: 21903322 DOI: 10.1016/j.canlet.2011.08.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 08/01/2011] [Accepted: 08/10/2011] [Indexed: 11/24/2022]
Abstract
Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity of troglitazone (TGZ) and its mechanisms in terms of PPARγ dependency and the p38 mitogen-activated protein kinase (MAPK) pathway in three human renal cell carcinoma (RCC) cell lines, 786-O, Caki-2 and ACHN cells. TGZ induced apoptosis and exerted cytotoxicity in a PPARγ-independent manner. We demonstrated that TGZ activated the p38 MAPK pathway and was involved in the cytotoxicity of TGZ. It was also revealed that TGZ induced G(2)/M cell cycle arrest through activation of p38 MAPK.
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PPARgamma and Apoptosis in Cancer. PPAR Res 2011; 2008:704165. [PMID: 18615184 PMCID: PMC2442903 DOI: 10.1155/2008/704165] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Revised: 04/21/2008] [Accepted: 06/11/2008] [Indexed: 12/22/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand binding transcription factors which function in many physiological roles including lipid metabolism, cell growth, differentiation, and apoptosis. PPARs and their ligands have been shown to play a role in cancer. In particular, PPARγ ligands including endogenous prostaglandins and the synthetic thiazolidinediones (TZDs) can induce apoptosis of cancer cells with antitumor activity. Thus, PPARγ ligands have a potential in both chemoprevention and therapy of several types of cancer either as single agents or in combination with other antitumor agents. Accordingly, the involvement of PPARγ and its ligands in regulation of apoptosis of cancer cells have been extensively studied. Depending on cell types or ligands, induction of apoptosis in cancer cells by PPARγ ligands can be either PPARγ-dependent or -independent. Through increasing our understanding of the mechanisms of PPARγ ligand-induced apoptosis, we can develop better strategies which may include combining other antitumor agents for PPARγ-targeted cancer chemoprevention and therapy. This review will highlight recent research advances on PPARγ and apoptosis in cancer.
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Ferrara A, Lewis JD, Quesenberry CP, Peng T, Strom BL, Van Den Eeden SK, Ehrlich SF, Habel LA. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care 2011; 34:923-9. [PMID: 21447664 PMCID: PMC3064052 DOI: 10.2337/dc10-1067] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To explore whether treatment with pioglitazone was associated with risk of incident cancer at the 10 most common sites (prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma [NHL], pancreas, kidney/renal pelvis, rectal, and melanoma). RESEARCH DESIGN AND METHODS A cohort study of 252,467 patients aged ≥40 years from the Kaiser Permanente Northern California Diabetes Registry was conducted. All prescriptions for diabetes medications were identified by pharmacy records. Cox proportional hazards models were used to examine the association between risk of incident cancer and ever use, duration, dose, and time since initiation of pioglitazone (modeled as time-dependent variables). RESULTS In models adjusted for age, sex, year of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, and use of other diabetes medications, the hazard ratio (HR) for each cancer associated with ever use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. There was a suggestion of an increased risk of melanoma (HR 1.3 [95% CI 0.9-2.0]) and NHL (1.3 [1.0-1.8]) and a decreased risk of kidney/renal pelvis cancers (0.7 [0.4-1.1]) associated with ever use of pioglitazone. These associations were unaltered with increasing dose, duration, or time since first use. CONCLUSIONS We found no clear evidence of an association between use of pioglitazone and risk of the incident cancers examined. Because the maximum duration of follow-up was fewer than 6 years after the initiation of pioglitazone, longer-term studies are needed.
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Affiliation(s)
- Assiamira Ferrara
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
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22
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Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells. Cancer Lett 2010; 300:134-44. [PMID: 21067863 DOI: 10.1016/j.canlet.2010.09.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2010] [Revised: 09/11/2010] [Accepted: 09/16/2010] [Indexed: 11/21/2022]
Abstract
The present study was performed to investigate the possible combined use of the Cox-2 inhibitor niflumic acid and the PPARγ ligand ciglitazone and to elucidate the mechanisms underlying enhanced apoptosis by this combination treatment in human lung cancer cells. Combined niflumic acid-ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis. In addition, combined niflumic acid-ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid-ciglitazone treatment-induced activation of caspase-8 and caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in caspase-8 activation and apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid-ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and caspase-8 activation are critical in combined niflumic acid-ciglitazone treatment-induced apoptosis in human lung cancer cells.
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Hardy KD, Cox BE, Milne GL, Yin H, Roberts LJ. Nonenzymatic free radical-catalyzed generation of 15-deoxy-Δ(12,14)-prostaglandin J₂-like compounds (deoxy-J₂-isoprostanes) in vivo. J Lipid Res 2010; 52:113-24. [PMID: 20944061 DOI: 10.1194/jlr.m010264] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
15-Deoxy-Δ(12,14)-prostaglandin J₂ (15-d-PGJ₂) is a reactive cyclopentenone eicosanoid generated from the dehydration of cyclooxygenase-derived prostaglandin D₂ (PGD₂). This compound possesses an α,β-unsaturated carbonyl moiety that can readily adduct thiol-containing biomolecules such as glutathione and cysteine residues of proteins via the Michael addition. Due to its reactivity, 15-d-PGJ₂ is thought to modulate inflammatory and apoptotic processes and is believed to be an endogenous ligand for peroxisome proliferator-activated receptor-γ. However, the extent to which 15-d-PGJ₂ is formed in vivo and the mechanisms that regulate its formation are unknown. Previously, we have reported the formation of PGD₂ and PGJ₂-like compounds, termed D₂/J₂-isoprostanes (D₂/J₂-IsoPs), produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid (AA). Based on these findings, we investigated whether 15-d-PGJ₂-like compounds are also formed via this nonenzymatic pathway. Here we report the generation of novel 15-d-PGJ₂-like compounds, termed deoxy-J₂-isoprostanes (deoxy-J₂-IsoPs), in vivo, via the nonenzymatic peroxidation of AA. Levels of deoxy-J₂-IsoPs increased 12-fold (6.4 ± 1.1 ng/g liver) in rats after oxidant insult by CCl₄ treatment, compared with basal levels (0.55 ± 0.21 ng/g liver). These compounds may have important bioactivities in vivo under conditions associated with oxidant stress.
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Affiliation(s)
- Klarissa D Hardy
- Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33:1674-85. [PMID: 20587728 PMCID: PMC2890380 DOI: 10.2337/dc10-0666] [Citation(s) in RCA: 1452] [Impact Index Per Article: 96.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis, 2) risk factors common to both diabetes and cancer, 3) possible biologic links between diabetes and cancer risk, and 4) whether diabetes treatments influence risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed.
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Affiliation(s)
- Edward Giovannucci
- Department of Nutrition, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
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New troglitazone derivatives devoid of PPARγ agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines. Breast Cancer Res Treat 2010; 124:101-10. [PMID: 20054646 DOI: 10.1007/s10549-009-0700-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Accepted: 12/16/2009] [Indexed: 01/10/2023]
Abstract
Numerous recent studies indicate that most anticancer effects of PPARγ agonists like thiazolidinediones are the result of PPARγ-independent pathways. These conclusions were obtained by several approaches including the use of thiazolidinedione derivatives like Δ2-Troglitazone (Δ2-TGZ) that does not activate PPARγ. Since biotinylation has been proposed as a mechanism able to increase the specificity of drug delivery to cancer cells which could express a high level of vitamin receptor, a biotinylated derivative of Δ2-TGZ (bΔ2-TGZ) has been synthetized. In the present article, we have studied the in vitro effects of this molecule on both hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cells. In both cell lines, bΔ2-TGZ was more efficient than Δ2-TGZ to decrease cell viability. bΔ2-TGZ was also more potent than Δ2-TGZ to induce the proteasomal degradation of cyclin D1 in both cell lines and those of ERα in MCF-7 cells. However, in competition experiments, the presence of free biotin in the culture medium did not decrease the antiproliferative action of bΔ2-TGZ. Besides, other compounds that had no biotin but that were substituted at the same position of the phenolic group of the chromane moiety of Δ2-TGZ decreased cell viability similarly to bΔ2-TGZ. Hence, we concluded that the increased antiproliferative action of bΔ2-TGZ was not due to biotin itself but to the functionalization of the terminal hydroxyl group. This should be taken into account for the design of new thiazolidinedione derivatives able to affect not only hormone-dependent but also hormone-independent breast cancer cells in a PPARγ-independent pathway.
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15-Deoxi-Δ12,14-prostaglandin J2 is a tubulin-binding agent that destabilizes microtubules and induces mitotic arrest. Biochem Pharmacol 2009; 78:1330-9. [DOI: 10.1016/j.bcp.2009.06.100] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Revised: 06/18/2009] [Accepted: 06/24/2009] [Indexed: 11/17/2022]
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Ma XM, Yu H, Huai N. Peroxisome proliferator-activated receptor-γ is essential in the pathogenesis of gastric carcinoma. World J Gastroenterol 2009; 15:3874-83. [PMID: 19701967 PMCID: PMC2731249 DOI: 10.3748/wjg.15.3874] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether peroxisome proliferator-activated receptor γ (PPAR-γ) is expressed in human gastric carcinoma and whether PPAR-γ is a potential target for gastric carcinoma therapy.
METHODS: PPAR-γ protein in gastric carcinoma was examined by immunohistochemistry. In the gastric carcinoma cell line MGC803, PPAR-γ, survivin, Skp2 and p27 protein and mRNA were examined by Western blotting and real-time reverse transcription-polymerase chain reaction, respectively; proliferation was examined by MTT; apoptosis was examined by chromatin staining with Hoechst 33342 and fluorescence activated cell sorting (FACS). and cell cycle was examined by FACS; the knockdown of PPAR-γ was done by RNA interference.
RESULTS: A high level of expression of PPAR-γ was observed in human gastric carcinoma and in a human gastric carcinoma cell line MGC803. The PPAR-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibited growth, and induced apoptosis and G1/G0 cell cycle arrest in MGC803 cells in a concentration-dependent and time-dependent manner. The effect of 15d-PGJ2 on MGC803 cells was not reversed by the selective and irreversible antagonist GW9662 for PPAR-γ. Furthermore, survivin and Skp2 expression were decreased, whereas p27 expression was enhanced following 15d-PGJ2 treatment in a dose-dependent manner in MGC803 cells. Interestingly, we also found that small interfering RNA for PPAR-γ inhibited growth and induced apoptosis in MGC803 cells. The inhibition of PPAR-γ function may be a potentially important and novel modality for treatment and prevention of gastric carcinoma.
CONCLUSION: A PPAR-γ agonist inhibited growth of human gastric carcinoma MGC803 cells by inducing apoptosis and G1/G0 cell cycle arrest with the involvement of survivin, Skp2 and p27 and not via PPAR-γ.
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Zhou J, Zhang W, Liang B, Casimiro MC, Whitaker-Menezes D, Wang M, Lisanti MP, Lanza-Jacoby S, Pestell RG, Wang C. PPARgamma activation induces autophagy in breast cancer cells. Int J Biochem Cell Biol 2009; 41:2334-42. [PMID: 19563910 DOI: 10.1016/j.biocel.2009.06.007] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2009] [Accepted: 06/22/2009] [Indexed: 12/19/2022]
Abstract
It has been previously shown that PPAR gamma ligands induce apoptotic cell death in a variety of cancer cells. Given the evidence that these ligands have a receptor-independent function, we further examined the specific role of PPAR gamma activation in this biological process. Surprisingly, we failed to demonstrate that MDA-MB-231 breast cancer cells undergo apoptosis when treated with sub-saturation doses of troglitazone and rosiglitazone, which are synthetic PPAR gamma ligands. Acridine orange (AO) staining showed acidic vesicular formation within ligand-treated cells, indicative of autophagic activity. This was confirmed by autophagosome formation as indicated by redistribution of LC3, an autophagy-specific protein, and the appearance of double-membrane autophagic vacuoles by electron microscopy following exposure to ligand. To determine the mechanism by which PPAR gamma induces autophagy, we transduced primary mammary epithelial cells with a constitutively active mutant of PPAR gamma and screened gene expression associated with PPAR gamma activation by genome-wide array analysis. HIF1 alpha and BNIP3 were among 42 genes up-regulated by active PPAR gamma. Activation of PPAR gamma induced HIF1 alpha and BNIP3 protein and mRNA abundance. HIF1 alpha knockdown by shRNA abolished the autophagosome formation induced by PPAR gamma activation. In summary, our data shows a specific induction of autophagy by PPAR gamma activation in breast cancer cells providing an understanding of distinct roles of PPAR gamma in tumorigenesis.
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Affiliation(s)
- Jie Zhou
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
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Jung WK, Park IS, Park SJ, Yea SS, Choi YH, Oh S, Park SG, Choi IW. The 15-deoxy-Delta12,14-prostaglandin J2 inhibits LPS-stimulated AKT and NF-kappaB activation and suppresses interleukin-6 in osteoblast-like cells MC3T3E-1. Life Sci 2009; 85:46-53. [PMID: 19409914 DOI: 10.1016/j.lfs.2009.04.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 04/03/2009] [Accepted: 04/21/2009] [Indexed: 12/29/2022]
Abstract
AIMS Periodontitis is a chronic inflammatory disease that results in gingival inflammation and periodontal tissue destruction and is accompanied by alveolar bone resorption and eventual tooth loss. We examined the effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) on periodontitis by inhibiting the production of interleukin-6 (IL-6). MAIN METHODS Osteoblast-like cells MC3T3E-1 were pretreated with 15d-PGJ(2) before being incubated with lipopolysaccharide (LPS), the effect of 15d-PGJ(2) on IL-6 production, expression and its regulatory mechanisms were studied by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, electrophoretic mobility shift assay (EMSA), and confocal laser scanning microscopy study. KEY FINDINGS 15d-PGJ(2) inhibits LPS-stimulated IL-6 production in a concentration-dependent manner in osteoblast-like cells MC3T3E-1, without appreciable cytotoxicity. To further examine the mechanism responsible for the inhibition of IL-6 production by 15d-PGJ(2), we examined the effect of 15d-PGJ(2) on nuclear factor-kappaB (NF-kappaB) activation and the phosphorylation of protein kinase B (Akt). 15d-PGJ(2) treatment clearly reduced the DNA binding activity of NF-kappaB in LPS-stimulated osteoblast-like cells MC3T3E-1, an effect that was mediated by inhibiting the degradation of inhibitor kappaB (IkappaB) and nuclear translocation of NF-kappaB p65 subunit. In addition, 15d-PGJ(2) attenuated the LPS-mediated Akt pathway. These effects of 15d-PGJ(2) were not abrogated by the PPARgamma antagonist, GW9662, indicating that they are PPARgamma-independent actions. SIGNIFICANCE These results suggest that 15d-PGJ(2) possess a potent suppressive effect on inflammatory responses of osteoblast-like cells MC3T3E-1 via the Akt and NF-kappaB pathways independent of PPARgamma and suggest that this compound may offer some insight into the development of a new therapeutic approach to the prevention and treatment of periodontal diseases.
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Affiliation(s)
- Won-Kyo Jung
- Department of Marine Life Science, Chosun University, Gwangju, Republic of Korea
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Choi CH, Kwon CH, Kim YK. The PPARγ Agonist Rosiglitazone Inhibits Glioma Cell Proliferation and Migrationin vitroand Glioma Tumor Growthin vivo. Exp Neurobiol 2009. [DOI: 10.5607/en.2009.18.2.112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Chang Hwa Choi
- Department of Neurosurgery, Pusan National University College of Medicine, Busan 602-739, Korea
| | - Chae Hwa Kwon
- Department of Physiology, Pusan National University College of Medicine, Busan 602-739, Korea
| | - Yong Keun Kim
- Department of Physiology, Pusan National University College of Medicine, Busan 602-739, Korea
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31
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Zaytseva YY, Wang X, Southard RC, Wallis NK, Kilgore MW. Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells. Mol Cancer 2008; 7:90. [PMID: 19061500 PMCID: PMC2614423 DOI: 10.1186/1476-4598-7-90] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2008] [Accepted: 12/05/2008] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPARgamma has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPARgamma signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies are inconsistent and suggest that endogenous activation of PPARgamma plays a much more complex role in initiation and progression of cancer than previously thought. RESULTS We have previously demonstrated that an increase in expression of PPARgamma1 in MCF-7 breast cancer cells is driven by a tumor-specific promoter. Myc-associated zinc finger protein (MAZ) was identified as a transcriptional mediator of PPARgamma1 expression in these cells. In this study, using RNA interference (RNAi) to inhibit PPARgamma1 expression directly or via down-regulation of MAZ, we report for the first time that a decrease in PPARgamma1 expression results in reduced cellular proliferation in MCF-7 breast cancer cells. Furthermore, we demonstrate that these changes in proliferation are associated with a significant decrease in cell transition from G1 to the S phase. Using a dominant-negative mutant of PPARgamma1, Delta462, we confirmed that PPARgamma1 acts as a pro-survival factor and showed that this phenomenon is not limited to MCF-7 cells. Finally, we demonstrate that down-regulation of PPARgamma1 expression leads to an induction of apoptosis in MCF-7 cells, confirmed by analyzing Bcl-2 expression and PARP-1 cleavage. CONCLUSION Thus, these findings suggest that an increase in PPARgamma1 signaling observed in breast cancer contributes to an imbalance between proliferation and apoptosis, and may be an important hallmark of breast tumorigenesis. The results presented here also warrant further investigation regarding the use of PPARgamma ligands in patients who are predisposed or already diagnosed with breast cancer.
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Affiliation(s)
- Yekaterina Y Zaytseva
- Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY 40536-0298, USA.
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32
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Au-Yeung KKW, Liu PL, Chan C, Wu WY, Lee SST, Ko JKS. Herbal isoprenols induce apoptosis in human colon cancer cells through transcriptional activation of PPARgamma. Cancer Invest 2008; 26:708-17. [PMID: 18608213 DOI: 10.1080/07357900801898656] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Farnesol (FOH) and geranylgeraniol (GGOH) possess anti-tumor potential, while peroxisome proliferator-activated receptor gamma (PPARgamma) has exhibited modulating effects in colorectal cancers. We investigated the anti-carcinogenic effects of these isoprenols in HT-29 and HCT116 colon cancer cells and PPARgamma involvement. Results indicate that the FOH- and GGOH-induced apoptosis involve caspase 3 activation, PARP cleavage, nuclear chromatin condensation, down-regulation of Bcl-x(L) and survivin expression, with increased PPARgamma promoter activity. Pretreatment of the PPARgamma antagonist GW9662 reduces FOH-induced growth inhibition and the associated PARP cleavage. We conclude that PPARgamma activation is essential to elicit the anti-carcinogenic action of herbal isoprenols in colonic cancer cells.
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Affiliation(s)
- Kathy Ka-Wai Au-Yeung
- Pharmacology and Toxicology Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
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33
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Hong J, Samudio I, Chintharlapalli S, Safe S. 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes decrease mitochondrial membrane potential and induce apoptosis in endometrial and other cancer cell lines. Mol Carcinog 2008; 47:492-507. [PMID: 18085536 PMCID: PMC2711558 DOI: 10.1002/mc.20407] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes, containing p-t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC(6)H(5)) substituents, are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists; however, DIM-C-pPhtBu-induced growth inhibition and cell death in human HEC1A endometrial cancer cells is PPARgamma-independent. DIM-C-pPhtBu decreased mitochondrial membrane potential (MMP) and promoted the release of cytochrome c and caspase activation and nuclear uptake of endonuclease G leading to apoptosis of HEC1A cells. DIM-C-pPhtBu specifically targeted the mitochondrial permeability transition pore complex (PTPC) because the DIM-C-pPhtBu-induced pro-apoptotic responses were inhibited by atractyloside (Atra), a compound that specifically interacts with the inner mitochondrial membrane adenine nucleotide transport (ANT) proteins. At the dose of Atra used in this study (300 microM), this compound alone did not alter the PTPC but inhibited the mitochondriotoxic effects of DIM-C-pPhtBu. DIM-C-pPhtBu/DIM-C-pPhC(6)H(5) and Atra also differentially affected the ability of eosin-5-maleimide (EMA) to alkylate Cys160 in the ANT protein and Atra, but not DIM-C-pPhtBu, inhibited the exchange of ATP/ADP in isolated mitochondria suggesting that these pharmacophores act on different sites on the ANT protein. Results of this study show that the receptor-independent proapoptotic activity of DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) were related to novel mitochondriotoxic activities involving inner mitochondrial ANT proteins.
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Affiliation(s)
- Jun Hong
- Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77843-4466, USA
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34
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Vanderlaag K, Su Y, Frankel AE, Grage H, Smith R, Khan S, Safe S. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways. Breast Cancer Res Treat 2008; 109:273-283. [PMID: 17624585 DOI: 10.1007/s10549-007-9648-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2007] [Accepted: 06/07/2007] [Indexed: 10/23/2022]
Abstract
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing para-trifluoromethyl (DIM-C-pPhCF(3)), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC(6)H(5)) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor gamma (PPARgamma) in estrogen receptor alpha-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G(0)/G(1) to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor beta-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARgamma antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB-231 cells as xenografts and treated with DIM-C-pPhC(6)H(5) (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER-negative breast cancer.
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Affiliation(s)
- Kathy Vanderlaag
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
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35
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Accumulation of 15-deoxy-delta(12,14)-prostaglandin J2 adduct formation with Keap1 over time: effects on potency for intracellular antioxidant defence induction. Biochem J 2008; 411:297-306. [PMID: 18237271 DOI: 10.1042/bj20071189] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The COX (cyclo-oxygenase) pathway generates the reactive lipid electrophile 15d-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2), which forms covalent protein adducts that modulate cell signalling pathways. It has been shown that this regulates important biological responses, including protection against oxidative stress, and supports the proposal that 15d-PGJ2 has pharmacological potential. Protective pathways activated by 15d-PGJ2 include those controlling the synthesis of the intracellular antioxidants GSH and the enzyme HO-1 (haem oxygenase-1). The induction of the synthesis of these intracellular antioxidants is, in large part, regulated by covalent modification of Keap1 (Kelchlike erythroid cell-derived protein with 'capn'collar homologyassociated protein 1) by the lipid and the subsequent activation of the EpRE (electrophile-response element). For the first time, we show that the potency of 15d-PGJ2 as a signalling molecule in endothelial cells is significantly enhanced by the accumulation of the covalent adduct with 15d-PGJ2 and endogenous Keap1 over the time of exposure to the prostaglandin. The consequence of this finding is that signalling initiated by electrophilic lipids differs from agonists that do not form covalent adducts with proteins because the constant generation of very lowconcentrations of 15d-PGJ2 can lead to induction of GSH or HO-1. In the course of these studies we also found that a substantial amount (97-99%) of exogenously added 15d-PGJ2 is inactivated in the medium and does not enter the cells to initiate cell signalling. In summary, we propose that the accumulation of covalent adduct formation with signalling proteins provides a mechanism through which endogenous intracellular formation of electrophilic lipids from COX can exert an anti-inflammatory effect in vivo.
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36
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Lee SJ, Kim MS, Park JY, Woo JS, Kim YK. 15-Deoxy-delta 12,14-prostaglandin J2 induces apoptosis via JNK-mediated mitochondrial pathway in osteoblastic cells. Toxicology 2008; 248:121-9. [PMID: 18450357 DOI: 10.1016/j.tox.2008.03.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2008] [Revised: 03/17/2008] [Accepted: 03/18/2008] [Indexed: 11/15/2022]
Abstract
The cyclopentenone prostaglandin 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) induces apoptosis in various cell types. However, the underlying mechanism of 15d-PGJ2-induced apoptosis is not fully understood. The present study was undertaken to determine the molecular mechanism by which 15d-PGJ2 induces apoptosis in MC3T3-E1 mouse osteoblastic cells. 15d-PGJ2 caused a concentration- and time-dependent apoptotic cell death. 15d-PGJ2 induced a transient activation of ERK1/2 and sustained activation of JNK. 15d-PGJ2-induced cell death was prevented by the JNK inhibitor SP6001, but not by inhibitors of ERK1/2 and p38. JNK activation by 15d-PGJ2 was blocked by antioxidants N-acetylcysteine (NAC) and GSH. 15d-PGJ2 caused ROS generation and 15d-PGJ2-induced cell death was prevented by antioxidants, suggesting involvement of ROS generation in 15d-PGJ2-induced cell death. 15d-PGJ2 triggered the mitochondrial apoptotic pathway indicated by enhanced Bax expression, loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation. The JNK inhibitor blocked these events induced by 15d-PGJ2. Taken together, these results suggest that the 15d-PGJ2 induces cell death through the mitochondrial apoptotic pathway dependent of ROS and JNK activation in osteoblastic cells.
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Affiliation(s)
- Sung Ju Lee
- Department of Physiology, College of Medicine, Pusan National University, Pusan 602-739, Republic of Korea
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37
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Wu W, Celestino J, Milam MR, Schmeler KM, Broaddus RR, Ellenson LH, Lu KH. Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. Int J Gynecol Cancer 2008; 18:329-38. [PMID: 18334011 DOI: 10.1111/j.1525-1438.2007.01002.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PTEN mutations have been implicated in the development of endometrial hyperplasia and subsequent cancer. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists have demonstrated antineoplastic and chemopreventive effects. The purpose of this study was to evaluate the effects of the PPAR-gamma agonist rosiglitazone on both PTEN wild type and PTEN null cell lines and in the PTEN heterozygote((+/-)) murine model. Hec-1-A (PTEN wild type) and Ishikawa (PTEN null) cells were treated with rosiglitazone. Thirty-five female PTEN(+/-) mice were genotyped and placed into one of four groups for treatment for 18 weeks: A) PTEN wild type with 4 mg/kg rosiglitazone, B) PTEN(+/-) mice with vehicle, C) PTEN(+/-) mice with 4 mg/kg rosiglitazone, and D) PTEN(+/-) mice with 8 mg/kg rosiglitazone. Proliferation and apoptosis were measured by bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragmentation sites assay. Rosiglitazone caused cell growth inhibition in both Hec-1-A and Ishikawa in a dose-dependent manner (P < 0.02 and P < 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A (P < .001) and Ishikawa (P < .001) cells in a dose-dependent manner. In the murine model, rosiglitazone decreased proliferation of the endometrial hyperplastic lesions (B vs C; 39.7% vs 9.3% and B vs D; 39.7% vs 4.2%; P < 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P < 0.0001 and B vs D; 2.8% vs 30.2%; P = 0.003). PPAR-gamma agonist rosiglitazone inhibits proliferation and induces apoptosis in both PTEN intact and PTEN null cancer cell lines and in hyperplastic endometrial lesions in the PTEN(+/)(-)murine model.
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Affiliation(s)
- W Wu
- Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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38
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Ferreira-Silva V, Rodrigues AC, Hirata TDC, Hirabara SM, Curi R. Effects of 15-deoxy-Δ12, 14 prostaglandin J2 and ciglitazone on human cancer cell cycle progression and death: The role of PPARγ. Eur J Pharmacol 2008; 580:80-6. [DOI: 10.1016/j.ejphar.2007.11.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 10/24/2007] [Accepted: 11/03/2007] [Indexed: 01/01/2023]
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39
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Papineni S, Chintharlapalli S, Safe S. Methyl 2-cyano-3,11-dioxo-18 beta-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor-gamma agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells. Mol Pharmacol 2008; 73:553-565. [PMID: 17989348 DOI: 10.1124/mol.107.041285] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025] Open
Abstract
Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-diene-30-oate (beta-CDODA-Me) is a synthetic analog of the naturally occurring triterpenoid glycyrrhetinic acid, which contains a 2-cyano substituent in the A-ring. beta-CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC(50) approximately 1 muM) and activated peroxisome proliferator-activated receptor gamma (PPARgamma), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPARgamma. beta-CDODA-Me induced p21 and p27, down-regulated cyclin D1 protein expression, and induced two other proapoptotic proteins, namely nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3. However, induction of these responses by beta-CDODA-Me was PPARgamma-independent and due to activation of phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and jun N-terminal kinase pathways by this compound. In contrast, beta-CDODA-Me also decreased androgen receptor (AR) and prostate-specific antigen (PSA) mRNA and protein levels through kinase-independent pathways. beta-CDODA-Me repressed AR mRNA transcription, whereas decreased PSA mRNA levels were dependent on protein synthesis and were reversed by cycloheximide. Thus, potent inhibition of LNCaP cell survival by beta-CDODA-Me is due to PPARgamma-independent activation of multiple pathways that selectively activate growth-inhibitory and proapoptotic responses.
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Affiliation(s)
- Sabitha Papineni
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
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40
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Disruption of ERalpha signalling pathway by PPARgamma agonists: evidences of PPARgamma-independent events in two hormone-dependent breast cancer cell lines. Breast Cancer Res Treat 2008; 112:437-51. [PMID: 18204896 DOI: 10.1007/s10549-007-9886-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Accepted: 12/26/2007] [Indexed: 01/09/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that can be activated by natural ligands such as 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ(2)) as well as synthetic drugs such as thiazolidinediones. The treatment of human breast cancer cell lines with PPARgamma agonists is known to have antiproliferative effects but the role of PPARgamma activation in the process remains unclear. In the present study, we investigated the effects of four PPARgamma agonists, Rosiglitazone (RGZ), Ciglitazone (CGZ), Troglitazone (TGZ) and the natural agonist 15d-PGJ(2), on estrogen receptor alpha (ERalpha) signalling pathway in two hormone-dependent breast cancer cell lines, MCF-7 and ZR-75-1. In both of them, TGZ, CGZ and 15d-PGJ(2) induced an inhibition of ERalpha signalling associated with the proteasomal degradation of ERalpha. ZR-75-1 cells were more sensitive than MCF-7 cells to these compounds. Treatments that induced ERalpha degradation inhibited cell proliferation after 24 h. In contrast, 24 h exposure to RGZ, the most potent activator of PPARgamma disrupted neither ERalpha signalling nor cell proliferation. 9-cis retinoic acid never potentiated the proteasomal degradation of ERalpha. PPARgamma antagonists (T0070907, BADGE and GW 9662) did not block the proteolysis of ERalpha in MCF-7 and ZR-75-1 cells treated with TGZ. ERalpha proteolysis still occurred in case of PPARgamma silencing as well as in case of treatment with the PPARgamma-inactive compound Delta2-TGZ, demonstrating a PPARgamma-independent mechanism. The use of thiazolidinedione derivatives able to trigger ERalpha degradation by a PPARgamma-independent pathway could be an interesting tool for breast cancer therapy.
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Kang DW, Choi CH, Park JY, Kang SK, Kim YK. Ciglitazone Induces Caspase-Independent Apoptosis through Down-Regulation of XIAP and Survivin in Human Glioma Cells. Neurochem Res 2007; 33:551-61. [DOI: 10.1007/s11064-007-9475-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2007] [Accepted: 08/15/2007] [Indexed: 12/20/2022]
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Laidler P, Dulińska J, Mrozicki S. Does the inhibition of c-myc expression mediate the anti-tumor activity of PPAR’s ligands in prostate cancer cell lines? Arch Biochem Biophys 2007; 462:1-12. [PMID: 17466258 DOI: 10.1016/j.abb.2007.03.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2006] [Revised: 03/19/2007] [Accepted: 03/20/2007] [Indexed: 11/30/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands seem to induce anticancer effects on prostate cancer cells, but the mechanism is not clear. The effect of PPARgamma ligands omega-6 fatty acids and ciglitazone (2-15 microM)--on proliferation, and apoptosis of LNCaP, PC-3, DU145, CA-K and BPH-K cells was studied. PPARgamma ligands led to: (1) reduction of proliferation (20-50%) of all the studied cell lines, (2) stimulation of differentiation of prostate cancer cells through an increased expression (1.5-3-fold: LNCaP, DU145, BPH-K) or reexpression (PC-3, CA-K) of E-cadherin with parallel inhibition of N-cadherin expression (PC-3, CA-K) and (3) down-regulation (1-2-fold) of beta-catenin and c-myc expression. The selective PPARgamma antagonist GW9662 abolished the effect of those ligands on prostate cancer cells. These results suggest that inhibition of beta-catenin and in effect c-myc expression through activation of PPARgamma may help prostate cancer cells to restore several characteristics of normal prostate cells phenotype.
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Affiliation(s)
- Piotr Laidler
- Chair of Medical Biochemistry, Jagiellonian University Medical College, 31-034 Krakow, ul Kopernika 7, Poland.
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43
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Ou YC, Yang CR, Cheng CL, Raung SL, Hung YY, Chen CJ. Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. Eur J Pharmacol 2007; 563:49-60. [PMID: 17341418 DOI: 10.1016/j.ejphar.2007.01.071] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2006] [Revised: 01/24/2007] [Accepted: 01/24/2007] [Indexed: 12/21/2022]
Abstract
Studies on chemoprevention of cancer are generating increasing interest. The anti-neoplastic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) involves cyclooxygenase (COX)-dependent and COX-independent mechanisms. Evidence suggests that mitogen-activated protein kinases (MAPKs) may mediate apoptotic signaling induced by anti-neoplastic agents. While many reports have revealed the existence of MAPK activation in apoptosis induced by various stimuli, the signaling transduction pathways used by NSAIDs to trigger apoptosis in human renal cell carcinoma (RCC) remain largely unknown. Treatment of RCC 786-O cells with indomethacin resulted in growth regression and apoptosis. Caspase-dependent apoptosis was evidenced by the detection of enzymatic activities of caspase-3, caspase-6, and caspase-9 and suppression of toxicity using a caspase inhibitor. Indomethacin treatment was associated with increased expression of glucose-regulated protein 78 (GRP78) and C/EBP homologus protein (CHOP) and activation of ATF-6, characteristics of endoplasmic reticulum stress. In addition, the concomitant induction of peroxisome proliferator-activated receptor (PPAR), especially PPAR-beta, was apparent in treated cells. Western blotting revealed the activation of extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) with indomethacin treatment. Selective inhibitors of ERK, p38 MAPK, and JNK suppressed the induction of GRP78, CHOP, and PPAR-beta, attenuated indomethacin-induced cytotoxicity and reduced increased caspase activity. LY294002, a phosphoinositide-3 kinase (PI3K)/AKT inhibitor, and Trolox, an antioxidant, suppressed indomethacin-induced cytotoxicity and caspase activation. Furthermore, Trolox attenuated indomethacin-induced increased phosphorylation in ERK, p38 MAPK, JNK, and AKT. In conclusion, our findings establish a mechanistic link between the oxidative stress, PI3K/AKT pathway, MAPK pathway and indomethacin-induced cellular alterations and apoptosis in 786-O cells.
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Affiliation(s)
- Yen-Chuan Ou
- Division of Urology, Department of Education and Research, Taichung Veterans General Hospital, and Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan
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Yang YC, Tsao YP, Ho TC, Choung IP. Peroxisome proliferator-activated receptor-gamma agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines. Int J Gynecol Cancer 2007; 17:418-25. [PMID: 17316361 DOI: 10.1111/j.1525-1438.2006.00866.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARgamma agonists inhibit the growth of many types of cancers. To our knowledge, the effect of PPARgamma agonist on ovarian tumors is not reported. In this study, we used two human ovarian carcinoma cell lines (ES-2 and PA-1) to examine the effects of the PPARgamma agonists troglitazone (TGZ) and ciglitazone (CGZ) on cell survival. CGZ and TGZ inhibited viability in a dose-dependent manner in both types of ovarian cancer cells. The agonists also decreased cellular proliferation in association with an increase in the number of cells arrested in the G0/G1 phase of the cell cycle. Moreover, they increased apoptosis while increasing caspase-3 activity. Incubation of both the cell lines with the PPARgamma agonists led to upregulated PPARgamma expression. This effect appeared to be PPARgamma independent because the PPARgamma antagonist GW9662 did not reverse it. Along with the induction of apoptosis in ovarian cancer cells, protein expression levels of p53 and Bax markedly increased in response to the PPARgamma agonists. Our results demonstrated that PPARgamma agonists inhibited the viability of human ovarian cancer cells, at least partly by inducing apoptosis. As a result, these agonists may serve as future drugs for the prevention and treatment of ovarian cancer.
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Affiliation(s)
- Y-C Yang
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
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Su Y, Vanderlaag K, Ireland C, Ortiz J, Grage H, Safe S, Frankel AE. 1,1-Bis(3'-indolyl)-1-(p-biphenyl)methane inhibits basal-like breast cancer growth in athymic nude mice. Breast Cancer Res 2007; 9:R56. [PMID: 17764562 PMCID: PMC2206732 DOI: 10.1186/bcr1761] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Revised: 07/18/2007] [Accepted: 08/31/2007] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION 1,1-Bis (3'-indolyl)-1-(p-biphenyl) methane (CDIM9) has been identified as a new peroxisome proliferator-activated receptor (PPAR)-gamma agonist that exhibits both receptor dependent and independent antitumor activities. CDIM9 has not previously been studied with respect to its effects against basal-like breast cancer. Our goal in the present study was to investigate the anti-basal-like breast tumor activity of CDIM9 in vitro and in vivo. METHODS The effects of CDIM9 on cell protein and DNA syntheses were determined in basal-like breast cancer MDA-MB231 and BT549 cells in vitro. Maximum tolerated dose and dose-limited toxicity were determined in BalB/c mice, and antitumor growth activities were assessed in MDA-MB231 basal-like breast tumor xenografts in athymic nude mice. RESULTS CDIM9 exhibited selective cell cytotoxicity and anti-proliferation effects on basal-like breast cancer lines. In MDA-MB231 cell, CDIM9 induced caveolin-1 and p27 expression, which was significantly downregulated by co-treatment with the PPAR-gamma antagonist GW9662. Nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3 were upregulated by CDIM9 through a PPAR-gamma independent pathway. CDIM9 (40 mg/kg daily, intraperitoneally, for 35 days) inhibited the growth of subcutaneous MDA-MB231 tumor xenografts by 87%, and produced a corresponding decrease in proliferation index. Nearly half of the treated mice (46%) had complete durable remissions, confirmed by histology. The growth of an established tumor was inhibited by CDIM9 treatment (64 mg/kg daily, intraperitoneally, for 10 days), with a mean tumor growth inhibition of 67% as compared with controls. CDIM9 induced increases in tumor caveolin-1 and p27 in vivo, which may contribute to its antitumor activity in basal-like breast cancer. CONCLUSION CDIM9 showed potent antiproliferative effects on basal-like breast cancer cell in tissue culture and dramatic growth inhibition in animal models at safe doses. These findings justify further development of this drug for treatment of basal-like breast cancer.
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Affiliation(s)
- Yunpeng Su
- Scott & White Cancer Research Institute, South Airport Road, Temple, Texas 76502, USA
| | - Kathryn Vanderlaag
- Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466
| | - Courtney Ireland
- Scott & White Cancer Research Institute, South Airport Road, Temple, Texas 76502, USA
| | - Janelle Ortiz
- Scott & White Cancer Research Institute, South Airport Road, Temple, Texas 76502, USA
| | - Henry Grage
- Plantacor, Inc., 526 University Dr. East Suite 101A, College Station, Texas 77840 USA
| | - Stephen Safe
- Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466
| | - Arthur E Frankel
- Scott & White Cancer Research Institute, South Airport Road, Temple, Texas 76502, USA
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Ray DM, Morse KM, Hilchey SP, Garcia TM, Felgar RE, Maggirwar SB, Phipps RP, Bernstein SH. The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gamma-independent pathway. Exp Hematol 2006; 34:1202-11. [PMID: 16939813 DOI: 10.1016/j.exphem.2006.04.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2006] [Revised: 04/26/2006] [Accepted: 04/28/2006] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Ligands for the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) are emerging as a new class of antitumor agents. Herein, we investigated the triterpenoid CDDO, a PPAR gamma ligand, for its potential as an anticancer agent on human diffuse large B-cell lymphoma (DLBCL) cells. METHODS The ability of CDDO to induce apoptosis in human DLBCL cells of both the germinal center and activated B-cell subtypes was determined by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay, (3)H-thymidine incorporation, and Annexin-V/propidium iodide staining. Small molecule antagonists of PPAR gamma, transfection assays, DNA binding assays, immunofluorescence, Western blotting, and NF-kappaB inhibitors were utilized to determine the contribution of PPAR gamma and NF-kappaB to the cytotoxic effects of CDDO. RESULTS Human DLBCL cells express PPAR gamma and PPAR gamma is activated by CDDO. In both subtypes of DLBCL cells CDDO inhibited proliferation, was cytotoxic, and induced apoptosis. The ability of CDDO to kill DLBCL cells was found to be independent of PPAR gamma activation. Interestingly, CDDO exposure resulted in activation of the p50 and p65 subunits of NF-kappaB. Moreover, the combination of CDDO with NF-kappaB inhibitors resulted in enhanced DLBCL cell death, indicating that NF-kappaB activation was a prosurvival signal. CONCLUSION These findings support the potential of CDDO, alone or in combination with NF-kappaB inhibitors, as a novel therapy for patients with DLBCL.
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Affiliation(s)
- Denise M Ray
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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Sandig H, Pease JE, Sabroe I. Contrary prostaglandins: the opposing roles of PGD2 and its metabolites in leukocyte function. J Leukoc Biol 2006; 81:372-82. [PMID: 17043246 DOI: 10.1189/jlb.0706424] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Traditionally, PGD(2) has been considered to be a pro-inflammatory mediator, acting via classical PG receptors, such as the PGD(2) receptor (DP). PGD(2) is degraded rapidly in vitro and in vivo to a variety of metabolites, the majority of which were thought, until recently, to be physiologically inactive. Several "inactive" metabolites, particularly 15d-PGJ(2), have been shown to have wide-ranging effects on leukocytes and other cell types, however, and a potentially important anti-inflammatory role for PGD(2) has now been recognized, and the complexity of PGD(2) signaling is beginning to be elucidated. PGD(2) and its metabolites are biologically active over a broad concentration range, and, intriquingly, it appears that there are marked concentration-dependent variations in the consequences of signaling by these eicosanoids, which have the potential to exert pro- and anti-inflammatory effects. For example, the actions of PGD(2) can influence multiple stages in the life of the mature eosinophil, from causing its release from the bone marrow to inducing its recruitment and activation and, ultimately, regulating its apoptosis. This review is concerned with the diverse responses induced in leukocytes by PGD(2) and its metabolites and the signaling mechanisms which are thought to be responsible for them.
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Affiliation(s)
- Hilary Sandig
- Department of Asthma, Allergy and Respiratory Science, King's College London, 5th Floor Thomas Guy House, Guy's Hospital, London, UK.
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48
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Ray DM, Akbiyik F, Phipps RP. The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms. THE JOURNAL OF IMMUNOLOGY 2006; 177:5068-76. [PMID: 17015690 DOI: 10.4049/jimmunol.177.8.5068] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARgamma ligands, including the endogenous ligand 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARgamma for apoptosis induction is unknown. In this study, we used a PPARgamma dominant-negative approach and a small molecule irreversible PPARgamma antagonist and found that these inhibitors prevented PPARgamma activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARgamma agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARgamma but did not kill B lymphocytes, further supporting a non-PPARgamma-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARgamma may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARgamma agonists. Furthermore, these new findings support continued investigation into the use of PPARgamma agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.
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Affiliation(s)
- Denise M Ray
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
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49
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Cho WH, Choi CH, Park JY, Kang SK, Kim YK. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) Induces Cell Death Through Caspase-independent Mechanism in A172 Human Glioma Cells. Neurochem Res 2006; 31:1247-54. [PMID: 17006759 DOI: 10.1007/s11064-006-9157-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
15-Deoxy-(Delta12,14)-prostaglandin J(2) (15d-PGJ(2)) is a naturally occurring cyclopentenone metabolite of prostaglandin D(2) (PGD(2)) and is known as a specific potent ligand for the peroxisome proliferators activator receptor-gamma (PPARgamma). 15d-PGJ(2) inhibits cell growth and induces apoptosis in a number of different cancer cells. However, the underlying mechanism by which 15d-PGJ(2) induces cell death remains to be defined. The present study was undertaken to determine the effect of 15d-PGJ(2) on cell death in A172 human glioma cells. 15d-PGJ(2) caused reactive oxygen species (ROS) generation. 15d-PGJ(2)-induced ROS production and cell death were prevented by the antioxidant N-acetylcysteine. Activation of mitogen-activated protein kinases (MAPK) was not observed in cells treated with 15d-PGJ(2 )and inhibitors of MAPK subfamilies also were not effective in preventing 15d-PGJ(2)-induced cell death. 15d-PGJ(2) treatment caused mitochondrial dysfunction, as evidenced by depolarization of mitochondrial membrane potential. 15d-PGJ(2) induced caspase activation at 24 h of treatment, but the 15d-PGJ(2)-induced cell death was not prevented by caspase inhibitors. The antiapoptotic protein XIAP levels and release of apoptosis inducing factor (AIF) into the cytosol were not altered by 15d-PGJ(2) treatment. Taken together, these findings indicate that 15d-PGJ(2) triggers cell death through a caspase-independent mechanism and ROS production and disruption of mitochondrial membrane potential play an important role in the 15d-PGJ(2)-induced cell death in A172 human glioma cells.
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Affiliation(s)
- W H Cho
- Department of Neurosurgery, College of Medicine, Pusan National University, Pusan, 602-739, Korea
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Hampel JKA, Brownrigg LM, Vignarajah D, Croft KD, Dharmarajan AM, Bentel JM, Puddey IB, Yeap BB. Differential modulation of cell cycle, apoptosis and PPARgamma2 gene expression by PPARgamma agonists ciglitazone and 9-hydroxyoctadecadienoic acid in monocytic cells. Prostaglandins Leukot Essent Fatty Acids 2006; 74:283-93. [PMID: 16647253 DOI: 10.1016/j.plefa.2006.03.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2005] [Revised: 02/15/2006] [Accepted: 03/12/2006] [Indexed: 12/22/2022]
Abstract
We sought to compare the effects of the thiazolidinedione ciglitazone with the endogenous fatty acid PPARgamma agonists 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE), in U937 monocytic cells. Ciglitazone and 9-HODE inhibited cell proliferation and all three agonists increased cellular content of C18:0 fatty acids. Ciglitazone and 13-HODE resulted in an increased percentage of cells in S phase and ciglitazone reduced the percentage of cells in G2/M phase of cell cycle, whilst 9-HODE increased the percentage of cells in G0/1 and reduced the fraction in S and G2/M phases. 9-HODE selectively induced apoptosis in U937 cells, and increased PPARgamma2 gene expression. Induction of apoptosis by 9-HODE was not abrogated by the presence of the PPARgamma antagonist GW9662. Synthetic (TZD) and endogenous fatty acid ligands for PPARgamma, ciglitazone and 9- and 13-HODE, possess differential, ligand specific actions in monocytic cells to regulate cell cycle progression, apoptosis and PPARgamma2 gene expression.
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Affiliation(s)
- Jade K A Hampel
- School of Medicine and Pharmacology, University of Western Australia, Fremantle and Royal Perth Hospitals, Australia
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