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Li W, Xu Y, Zeng X, Tan J, Wang Y, Wu H, Li M, Yi C. Etiological relationship between lipid metabolism and endometrial carcinoma. Lipids Health Dis 2023; 22:116. [PMID: 37537560 PMCID: PMC10401764 DOI: 10.1186/s12944-023-01868-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023] Open
Abstract
Endometrial carcinoma (EC) has become one of the most common gynecological malignant neoplasms in developed countries worldwide. Studies have shown that this may be closely related to the abnormal metabolism of blood lipids, which was the most significant metabolic change in the human body in this cancer. In this review, we focus on the correlation between lipid metabolism and EC and discuss the evidence that abnormal lipid metabolism promotes an increase in EC growth and metabolism, as well as the regulatory mechanism and related signaling pathways involved in this relationship. In addition, we also discussed the research progress of targeted therapies and drug treatments for EC that act on lipid metabolism, and statins are expected to become adjuvant drugs for EC in the future. This review will provide a systematic view for a better understanding of the etiological relationship between lipid metabolism and EC and further open up new therapeutic possibilities and effective treatments for EC by targeting lipid metabolism.
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Affiliation(s)
- Wenzhe Li
- Department of Endocrinology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Yi Xu
- Department of Endocrinology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Xinling Zeng
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Jie Tan
- Department of Hematology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Ya Wang
- Department of Endocrinology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
- Department of Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
| | - Hongyan Wu
- Department of Endocrinology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Maokun Li
- Department of Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
| | - Cunjian Yi
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
- Department of Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
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Cai X, Wang R, Tan J, Meng Z, Li N. Mechanisms of regulating NIS transport to the cell membrane and redifferentiation therapy in thyroid cancer. Clin Transl Oncol 2021; 23:2403-2414. [PMID: 34100218 DOI: 10.1007/s12094-021-02655-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/28/2021] [Indexed: 11/29/2022]
Abstract
Iodine is an essential constituent of thyroid hormone. Active iodide accumulation in the thyroid is mediated by the sodium iodide symporter (NIS), comprising the first step in thyroid hormone biosynthesis, which relies on the functional expression of NIS on the cell membrane. The retention of NIS expressed in differentiated thyroid cancer (DTC) cells allows further treatment with post-operative radioactive iodine (RAI) therapy. However, compared with normal thyroid tissue, differentiated thyroid tumors usually show a decrease in the active iodide conveyance and NIS is generally retained within the cells, indicating that posttranslational protein transfer to the plasma membrane is abnormal. In recent years, through in vitro studies and studies of patients with DTC, various methods have been tested to increase the transport rate of NIS to the cell membrane and increase the absorption of iodine. An in-depth understanding of the mechanism of NIS transport to the plasma membrane could lead to improvements in RAI therapy. Therefore, in this review, we discuss the current knowledge concerning the post-translational mechanisms that regulate NIS transport to the cell membrane and the current status of redifferentiation therapy for patients with RAI-refractory (RAIR)-DTC.
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Affiliation(s)
- X Cai
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - R Wang
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - J Tan
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Z Meng
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - N Li
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
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Hydroxychloroquine Potentiates Apoptosis Induced by PPAR α Antagonist in 786-O Clear Cell Renal Cell Carcinoma Cells Associated with Inhibiting Autophagy. PPAR Res 2021; 2021:6631605. [PMID: 33959154 PMCID: PMC8075691 DOI: 10.1155/2021/6631605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 02/07/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the major pathological pattern of renal cell carcinoma. The ccRCC cells exhibit a certain degree of inherent drug resistance due to some genetic mutations. In recent years, peroxisome proliferator-activated receptor-α (PPARα) antagonists have been reported as a targeted therapeutic drug capable of inducing apoptosis and cell cycle arrest in the ccRCC cell line. Autophagy, which can be induced by stress in eukaryotic cells, plays a complex role in the proliferation, survival, and death of tumor cells. In our study, we found that the expression of PPARα was low in highly differentiated ccRCC tissues and 786-O cell line but high in poorly differentiated ccRCC tissues. The level of PPARα expression in ccRCC tissues is correlated to the grade of differentiation, but not to the sex or age of ccRCC patients. The findings also revealed that the PPARα antagonist GW6471 can lower cell viability and induce autophagy in the 786-O ccRCC cell line. This autophagy can be inhibited by hydroxychloroquine. When treated with a combination of hydroxychloroquine and GW6471, the viability of the 786-O cells was decreased further when compared to the treatment with GW6471 or hydroxychloroquine alone, and apoptosis was promoted. Meanwhile, when human kidney 2 cells were cotreated with hydroxychloroquine and GW6471, cell viability was only slightly influenced. Hence, our finding indicates that the combination of GW6471 and hydroxychloroquine may constitute a novel and potentially effective treatment for ccRCC. Furthermore, this approach is likely to be safe owing to its minimal effects on normal renal tissues.
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Liu J, Liu Y, Lin Y, Liang J. Radioactive Iodine-Refractory Differentiated Thyroid Cancer and Redifferentiation Therapy. Endocrinol Metab (Seoul) 2019; 34:215-225. [PMID: 31565873 PMCID: PMC6769341 DOI: 10.3803/enm.2019.34.3.215] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 08/29/2019] [Accepted: 09/04/2019] [Indexed: 01/12/2023] Open
Abstract
The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.
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Affiliation(s)
- Jierui Liu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanqing Liu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China
| | - Yansong Lin
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China.
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Mazaira GI, Zgajnar NR, Lotufo CM, Daneri-Becerra C, Sivils JC, Soto OB, Cox MB, Galigniana MD. The Nuclear Receptor Field: A Historical Overview and Future Challenges. NUCLEAR RECEPTOR RESEARCH 2018; 5:101320. [PMID: 30148160 PMCID: PMC6108593 DOI: 10.11131/2018/101320] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.
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Affiliation(s)
- Gisela I. Mazaira
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (1428), Argentina
| | - Nadia R. Zgajnar
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
| | - Cecilia M. Lotufo
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
| | | | - Jeffrey C. Sivils
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Olga B. Soto
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Marc B. Cox
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Mario D. Galigniana
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (1428), Argentina
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
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Nakashima Y, Miyagi-Shiohira C, Noguchi H, Omasa T. Atorvastatin Inhibits the HIF1α-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells. Mol Ther 2018; 26:1715-1734. [PMID: 29929789 PMCID: PMC6036234 DOI: 10.1016/j.ymthe.2018.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 06/04/2018] [Accepted: 06/07/2018] [Indexed: 12/31/2022] Open
Abstract
We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs.
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Affiliation(s)
- Yoshiki Nakashima
- Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima 770-8506, Japan; Department of Material and Life Science, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan.
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan
| | - Takeshi Omasa
- Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima 770-8506, Japan; Department of Material and Life Science, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
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Functional role of PPAR-γ on the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. Sci Rep 2017; 7:12671. [PMID: 28978936 PMCID: PMC5627284 DOI: 10.1038/s41598-017-12570-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 09/05/2017] [Indexed: 11/21/2022] Open
Abstract
Peroxisome proliferator-activated receptor (PPAR)-γ is involved in both normal physiological processes and pathology of various diseases. The purpose of this study was to explore the function and underlying mechanisms of PPAR-γ in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) proliferation and migration. In the present study, we found PPAR-γ expression was remarkably reduced in RA synovium patient compare with OA and normal, as well as it was low-expression in Adjuvant-induced arthritis (AA). Moreover, inhibition PPAR-γ expression by T0070907 (12.5 μM) or PPAR-γ siRNA could promote FLSs proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, except for TIPM-1. These date indicate that up-regulation of PPAR-γ may play a critical role in RA FLSs. Interestingly, co-incubation FLSs with Pioditazone (25 μM) and over expression vector with pEGFP-N1-PPAR-γ reduced proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, besides TIMP-1. Further study indicates that PPAR-γ may induce activation Wnt/β-catenin signaling. In short, these results indicate that PPAR-γ may play a pivotal role during FLSs activation and activation of Wnt/β-catenin signaling pathway.
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PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs. PPAR Res 2016; 2016:3038164. [PMID: 27799938 PMCID: PMC5069360 DOI: 10.1155/2016/3038164] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022] Open
Abstract
Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.
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Rai S, Bhatnagar S. Hyperlipidemia, Disease Associations, and Top 10 Potential Drug Targets: A Network View. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2016; 20:152-68. [DOI: 10.1089/omi.2015.0172] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Sneha Rai
- Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology, Dwarka, New Delhi, India
| | - Sonika Bhatnagar
- Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology, Dwarka, New Delhi, India
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10
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Jayaraj P, Sen S, Bhattacharya T, Arora J, Yadav S, Chhoker V, Kumar A, Dhanaraj PS, Yadavilli KS, Verma M. Clinical relevance of cyclooxygenase 2 and peroxisome proliferator-activated receptor γ in eyelid sebaceous gland carcinoma. Histopathology 2016; 69:268-75. [PMID: 26791964 DOI: 10.1111/his.12932] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
AIMS Sebaceous gland carcinoma (SGC) is a malignancy associated with the pilosebaceous unit, and occurs at ocular or non-ocular sites. Cyclooxygenases (COXs) are enzymes that are crucial for lipid metabolism. COX-2 is overexpressed in various cancers, and its inhibition by non-steroidal anti-inflammatory drugs is known to reduce the risk of many cancers. Peroxisome proliferator-activated receptor (PPAR)-γ is a transcription factor involved in adipogenesis. PPAR-γ is a potential therapeutic target for the treatment of malignant tumours, including colon carcinoma. The aim of this study was to explore the status of COX-2 and PPAR-γ as prognostic markers in human eyelid SGC. METHODS AND RESULTS The immunohistochemical expression of COX-2 and PPAR-γ was evaluated in 31 SGC cases. Cytoplasmic expression of COX-2 was detected in 80% of the SGC cases, and nuclear expression of PPAR-γ in 87%. There were significant correlations of PPAR-γ expression with well-differentiated SGC [19/21 (90%)] and of COX-2 overexpression with reduced disease-free survival (P = 0.0441, log rank analysis). COX-2 expression [odds ratio (OR) 3.82, 95% confidence interval (CI) 1.02-14.33, P = 0.046] and lymph node metastasis (OR 0.17, 95% CI 0.04-0.65, P = 0.009) emerged as significant risk factors in the univariate analysis. However, COX-2 expression did not emerge as a significant independent prognostic factor in multivariate analysis. CONCLUSIONS COX-2 is a potential marker for identifying high-risk SGC patients. Expression of PPAR-γ in eyelid SGC cases reflects terminal sebaceous differentiation. Inhibitors of COX-2 signalling and PPAR-γ agonists are both prospective novel therapeutic targets in the management of eyelid SGC patients.
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Affiliation(s)
- Perumal Jayaraj
- Department of Zoology, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Seema Sen
- Department of Ocular Pathology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Tanaya Bhattacharya
- Department of Zoology, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Juhi Arora
- Department of Biochemistry, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Sameeksha Yadav
- Department of Zoology, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Varsha Chhoker
- Department of Zoology, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Abhishek Kumar
- Department of Biological Sciences, Sri Venkateswara College, University of Delhi, New Delhi, India
| | | | - Kameshwar S Yadavilli
- Department of Biochemistry, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Mansi Verma
- Department of Zoology, Sri Venkateswara College, University of Delhi, New Delhi, India
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Funakoshi-Tago M, Hattori T, Ueda F, Tago K, Ohe T, Mashino T, Tamura H. A proline-type fullerene derivative inhibits adipogenesis by preventing PPARγ activation. Biochem Biophys Rep 2016; 5:259-265. [PMID: 28955832 PMCID: PMC5600428 DOI: 10.1016/j.bbrep.2016.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/14/2015] [Accepted: 01/05/2016] [Indexed: 11/17/2022] Open
Abstract
Obesity and its associated metabolic diseases represent some of the most rapidly expanding health issues worldwide, and, thus, the development of a novel chemical compound to suppress adipogenesis is strongly expected. We herein investigated the effects of water-soluble fullerene derivatives: a bis-malonic acid derivative and three types of proline-type fullerene derivatives, on adipogenesis using NIH-3T3 cells overexpressing PPARγ. One of the proline-type fullerene derivatives (P3) harboring three carboxy groups significantly inhibited lipid accumulation and the expression of adipocyte-specific genes, such as aP2, induced by the PPARγ agonist rosiglitazone. On the other hand, the bis-malonic acid derivative (M) and the 2 other proline-type fullerene derivatives (P1, P2), which have two carboxy groups, had no effect on PPARγ-mediated lipid accumulation or the expression of aP2. P3 fullerene also inhibited lipid accumulation induced by the combined stimulation with 3-isobutyl-1-methylxanthine (IBMX), dexamethasone, and insulin in 3T3-L1 preadipocytes. During the differentiation of 3T3-L1 cells into adipocytes, P3 fullerene did not affect the expression of C/EBPδ, C/EBPβ, or PPARγ, but markedly inhibited that of aP2 mRNA. These results suggest that P3 fullerene exhibits anti-obesity activity by preventing the activation of PPARγ.
Fullerene derivative inhibits the rosiglitazone-induced adipogenesis. Fullerene derivative inhibits the rosiglitazone-induced expression of aP2 mRNA. Fullerene derivative inhibits adipogenesis of 3T3-L1 preadipocyte. Fullerene derivative inhibits the activation of PPARγ in 3T3-L1 preadipocyte.
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Key Words
- Adipogenesis
- C/EBPs, CCAAT/enhancer-binding proteins
- DMSO, dimethyl sulfoxide
- FBS, fetal bovine serum
- Fullerene
- HIV, human immunodeficiency virus
- IBMX, 3-isobutyl-1-methylxanthine
- NF-κB, nuclear factor kappa B
- Obesity
- PBS, phosphate-buffered saline
- PPARγ
- PPARγ, peroxisome proliferator-activated receptor γ
- ROS, reactive oxygen species
- RT-PCR, reverse transcription-polymerase chain reaction.
- aP2, adipocyte Protein 2
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Affiliation(s)
- Megumi Funakoshi-Tago
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
- Correspondence to: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.Graduate School of Pharmaceutical Sciences, Keio University1-5-30 ShibakoenMinato-kuTokyo105-8512Japan
| | - Takahiro Hattori
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Fumihito Ueda
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Kenji Tago
- Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan
| | - Tomoyuki Ohe
- Department of Bioorganic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Tadahiko Mashino
- Department of Bioorganic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Hiroomi Tamura
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
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Aires V, Brassart B, Carlier A, Scagliarini A, Mandard S, Limagne E, Solary E, Martiny L, Tarpin M, Delmas D. A role for peroxisome proliferator-activated receptor gamma in resveratrol-induced colon cancer cell apoptosis. Mol Nutr Food Res 2014; 58:1785-94. [PMID: 24975132 DOI: 10.1002/mnfr.201300962] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 03/31/2014] [Accepted: 05/01/2014] [Indexed: 12/22/2022]
Abstract
SCOPE Resveratrol may function as a chemopreventive agent. A recent clinical study demonstrates a reduction in tumor cell proliferation in colorectal patients receiving repeated oral ingestion of resveratrol. However, gaps remain in our knowledge of the molecular mechanisms by which resveratrol exerts its chemopreventive effect. We have previously demonstrated that resveratrol induces apoptosis in colon cancer cells and that resveratrol can sensitize chemoresistant colon cancer cells to various drugs. Based on its ability to activate peroxisome proliferator-activated receptor gamma (PPARγ) in colon cancer cells, we sought to determine the implication of this nuclear transcription factor in resveratrol-induced apoptosis. METHODS AND RESULTS Transient transfection of cancer cells with a dominant-negative PPARγ mutant or treatment with a PPARγ antagonist (GW9662) reversed the inhibitory effect of resveratrol. Moreover, GW9662 prevented disruption of the cell cycle induced by resveratrol and consequently abrogated resveratrol-induced apoptosis. Tumor cell death was potentiated by combining resveratrol with rosiglitazone, a PPARγ agonist. CONCLUSION The results show that PPARγ plays a role in resveratrol-induced apoptosis of colon carcinoma cells. The combination of resveratrol with a PPARγ agonist could be a promising pharmacological approach for treatment of colorectal cancer.
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Affiliation(s)
- Virginie Aires
- Université de Bourgogne, Dijon, France; Centre de Recherche INSERM U866 - Equipe Chimiothérapie, Métabolisme Lipidique et Réponse Immunitaire Antitumorale, Dijon, France
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FOROOTAN FARZADS, FOROOTAN SHIVAS, MALKI MOHAMMEDI, CHEN DANQING, LI GANDI, LIN KE, RUDLAND PHILIPS, FOSTER CHRISTOPHERS, KE YOUQIANG. The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer. Int J Oncol 2013; 44:265-75. [DOI: 10.3892/ijo.2013.2166] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Accepted: 10/17/2013] [Indexed: 11/05/2022] Open
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14
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Avci CB, Dodurga Y, Gundogdu G, Caglar HO, Kucukatay V, Gunduz C, Satiroglu-Tufan NL. Regulation of URG4/URGCP and PPARα gene expressions after retinoic acid treatment in neuroblastoma cells. Tumour Biol 2013; 34:3853-7. [PMID: 23821302 DOI: 10.1007/s13277-013-0970-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 06/24/2013] [Indexed: 10/26/2022] Open
Abstract
Neuroblastoma (NB), originating from neural crest cells, is the most common extracranial tumor of childhood. Retinoic acid (RA) which is the biological active form of vitamin A regulates differentiation of NB cells, and RA derivatives have been used for NB treatment. PPARα (peroxisome proliferator-activated receptor) plays an important role in the oxidation of fatty acids, carcinogenesis, and differentiation. URG4/URGCP gene is a proto-oncogene and that overexpression of URG4/URGCP is associated with metastasis and tumor recurrence in osteosarcoma. It has been known that URG4/URGCP gene is an overexpressed gene in hepatocellular carcinoma and gastric cancers. This study aims to detect gene expression patterns of PPARα and URG4/URGCP genes in SH-SY5Y NB cell line after RA treatment. Expressions levels of PPARα and URG4/URGCP genes were analyzed after RA treatment for reducing differentiation in SH-SY5Y NB cell line. To induce differentiation, the cells were treated with 10 μM RA in the dark for 3-10 days. Gene expression of URG4/URGCP and PPARα genes were presented as the yield of polymerase chain reaction (PCR) products from target genes compared with the yield of PCR products from the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. SH-SY5Y cells possess small processes in an undifferentiated state, and after treatment with RA, the cells developed long neurites, resembling a neuronal phenotype. PPARα gene expression increased in RA-treated groups; URG4/URGCP gene expression decreased in SH-SY5Y cells after RA treatment compared with that in the control cells. NB cell differentiation might associate with PPARα and URG4/URGCP gene expression profile after RA treatment.
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Affiliation(s)
- Cigir Biray Avci
- Department of Medical Biology, School of Medicine, Ege University, Bornova, Izmir, 35100, Turkey,
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15
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Leclerc D, Cao Y, Deng L, Mikael LG, Wu Q, Rozen R. Differential gene expression and methylation in the retinoid/PPARA pathway and of tumor suppressors may modify intestinal tumorigenesis induced by low folate in mice. Mol Nutr Food Res 2012; 57:686-97. [PMID: 23001810 DOI: 10.1002/mnfr.201200212] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 06/20/2012] [Accepted: 06/25/2012] [Indexed: 01/01/2023]
Abstract
SCOPE Inadequate folate intake increases risk for colorectal cancer. We previously showed that low-folate diets induced intestinal tumors in BALB/c mice, but not in C57BL/6 mice. We suggested that DNA damage, altered methylation, and reduced apoptosis could contribute to tumorigenesis in this model. METHODS AND RESULTS To identify genes involved in tumorigenesis, we compared gene expression profiles in preneoplastic intestine of BALB/c and C57BL/6 mice-fed low folate. We identified 74 upregulated and 90 downregulated genes in BALB/c compared to C57BL/6 mice. We validated decreased expression of Bcmo1 and increased expression of Aldh1a, which would be expected to upregulate the peroxisome proliferator-activated receptor alpha (PPARA) pathway, and confirmed the expected upregulation of several Ppara downstream genes. We verified, in BALB/c mice, reduced expression of Sprr2a, a gene that increases resistance to oxidative damage, and of two oncosuppressors (Bmp5 and Arntl). Low folate increased Ppara and Aldh1a1 expression, and decreased Bcmo1, Sprr2a, and Bmp5 expression in BALB/c, compared to BALB/c on control diets. Bcmo1, Ppara, and Bmp5 showed differential DNA methylation related to strain, diet, and/or Mthfr genotype. CONCLUSION Disturbed regulation of the retinoid/PPARA pathway, which influences oxidative damage, and altered expression of tumor suppressors may contribute to intestinal tumorigenesis induced by low-folate intake.
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Affiliation(s)
- Daniel Leclerc
- Department of Human Genetics, Montreal Children's Hospital Research Institute, McGill University, Montreal, Canada
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16
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Lu W, Che P, Zhang Y, Li H, Zou S, Zhu J, Deng J, Shen X, Jiang H, Li J, Huang J. HL005--a new selective PPARγ antagonist specifically inhibits the proliferation of MCF-7. J Steroid Biochem Mol Biol 2011; 124:112-20. [PMID: 21296151 DOI: 10.1016/j.jsbmb.2011.01.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 01/26/2011] [Accepted: 01/28/2011] [Indexed: 11/30/2022]
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear transcription factor which is involved in many diseases, such as diabetes, inflammation, dyslipidemia, hypertension, and cancer. Recently, there are many reports showing that PPARγ agonists have preclinical and clinical anticancer activity, with relatively few reports on anticancer effects of PPARγ antagonists. From our compound library, a novel 3-thiazolinone-modified benzoic acid derivative HL005 is found as PPARγ selective ligand through SPR analysis (K(D)=0.21 μM), yeast two-hybrid results suggest that HL005 antagonize the potent PPARγ agonist rosiglitazone-induced recruitment of the coactivator for PPARγ (IC(50)=7.97 μM). Different from the most reported PPARγ antagonist, HL005 can inhibit the proliferation of MCF-7 cell line in a concentration-dependent manner and induce cell cycle arrest at G2/M phase, other than interference with cell adhesion. In order to study the binding mode of this compound, three derivatives are synthesized to get more detail about the structure-activity relationship, molecular docking and the NMR spectra indicate that similar to most PPARγ ligand, the carboxylic acid group is an important moiety for HL005 and contributes strong interaction with PPARγ.
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Affiliation(s)
- Weiqiang Lu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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17
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Han JS, Crowe DL. Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands. BMC Cancer 2010; 10:629. [PMID: 21080969 PMCID: PMC2999618 DOI: 10.1186/1471-2407-10-629] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2010] [Accepted: 11/16/2010] [Indexed: 12/28/2022] Open
Abstract
Background The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. Methods We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. Results SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. Conclusions These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.
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Affiliation(s)
- Ji Seung Han
- University of Illinois Cancer Center, Chicago, 60612, USA
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18
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Bonofiglio D, Cione E, Qi H, Pingitore A, Perri M, Catalano S, Vizza D, Panno ML, Genchi G, Fuqua SAW, Andò S. Combined low doses of PPARgamma and RXR ligands trigger an intrinsic apoptotic pathway in human breast cancer cells. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:1270-80. [PMID: 19644018 DOI: 10.2353/ajpath.2009.081078] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Ligand activation of peroxisome proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPARgamma ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor p53 and its effector p21(WAF1/Cip1). Functional experiments indicate that the nuclear factor-kappaB site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of p53 in PPARgamma/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPARgamma and RXR ligands may provide a therapeutic advantage in breast cancer treatment.
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Affiliation(s)
- Daniela Bonofiglio
- Faculty of Pharmacy Nutritional and Health Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
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Lindemann K, Vatten LJ, Ellstrøm-Engh M, Eskild A. The impact of BMI on subgroups of uterine cancer. Br J Cancer 2009; 101:534-6. [PMID: 19568239 PMCID: PMC2720238 DOI: 10.1038/sj.bjc.6605158] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background: Obesity increases the risk of uterine cancer, but results by histological type have differed. Methods: We followed 36 755 women for 17.8 years for uterine cancers. Results and conclusion: Body mass index (BMI) was positively associated with uterine cancers as a whole, particularly for endometrioid adenocarcinomas, for which the relative risk for very obese women (BMI: ⩾40 kg m−2) compared with lean (BMI: 20–24 kg m−2) women, was 11.1 (95% confidence interval: 5.2–23.8).
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Affiliation(s)
- K Lindemann
- Department of Obstetrics and Gynaecology, Akershus University Hospital, 1478 Lørenskog, Norway.
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20
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Lindemann K, Vatten LJ, Ellstrøm-Engh M, Eskild A. Serum lipids and endometrial cancer risk: Results from the HUNT-II study. Int J Cancer 2009; 124:2938-41. [DOI: 10.1002/ijc.24285] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Concurrent Endometrial Carcinoma in Patients with a Curettage Diagnosis of Endometrial Hyperplasia. J Formos Med Assoc 2009; 108:502-7. [DOI: 10.1016/s0929-6646(09)60098-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Chemopreventive efficacies of rosiglitazone, fenretinide and their combination against rat mammary carcinogenesis. Clin Transl Oncol 2009; 11:243-9. [DOI: 10.1007/s12094-009-0347-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Adrian TE, Hennig R, Friess H, Ding X. The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer. PPAR Res 2009; 2008:827096. [PMID: 19190780 PMCID: PMC2631651 DOI: 10.1155/2008/827096] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 10/22/2008] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B(4) receptor pathway and the PPARgamma pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B(4) receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPARgamma agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB(4) receptors and PPARgamma.
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Affiliation(s)
- Thomas E. Adrian
- Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
| | - Rene Hennig
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
- Department of Surgery, Technische Universitaet Muenchen, 81675 Munich, Germany
| | - Helmut Friess
- Department of Surgery, Technische Universitaet Muenchen, 81675 Munich, Germany
| | - Xianzhong Ding
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
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24
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Auyeung KKW, Ko JKS. Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell. Invest New Drugs 2009; 28:1-13. [PMID: 19139819 DOI: 10.1007/s10637-008-9207-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 12/03/2008] [Indexed: 01/01/2023]
Abstract
Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic property. We attempted to compare the anticarcinogenic mechanism of formononetin with that of the known proapoptotic flavonoid isoliquiritigenin (ISL) in human cancer cells. We first evaluated the effects of formononetin and ISL on HCT 116 colon cancer cell viability. Immunofluorescence staining was then performed to observe the morphological changes of cancer cells undergoing apoptosis, which had been substantiated using Annexin V-FITC/propidium iodide staining. Western immunoblotting and flow cytometry were also employed to study parameters associated with apoptosis and cell proliferation. Our data show that formononetin and ISL both inhibited the growth of colon cancer cells and promoted apoptosis. These processes were accompanied by caspase activation and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-x(L). Besides, the novel proapoptotic protein NSAID-activated gene (NAG-1) and its upstream regulator were overexpressed in drug-treated cells. Nevertheless, only ISL was found to induce a G2 arrest. These findings exemplify that both formononetin and ISL could cause growth inhibition and facilitate apoptosis in colon cancer cells, while only ISL is capable of inducing phase-specific cell cycle arrest. This suggests that the anticarcinogenic activities of different herbal flavonoids may involve both common and differential mechanisms of action, which could be developed as potential anticancer drugs.
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Affiliation(s)
- Kathy Ka-Wai Auyeung
- Pharmacology and Toxicology Laboratory, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong, China
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25
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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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Abstract
We examined the relationship of body mass index (BMI), diabetes and smoking to endometrial cancer risk in a cohort of 36 761 Norwegian women during 15.7 years of follow-up. In multivariable analyses of 222 incident cases of endometrial cancer, identified by linkage to the Norwegian Cancer Registry, there was a strong increase in risk with increasing BMI (P-trend <0.001). Compared to the reference (BMI 20–24 kg m−2), the adjusted relative risk (RR) was 0.53 (95% confidence interval (CI): 0.19–1.47) for BMI<20 kg m−2, 4.28 (95% CI: 2.58–7.09) for BMI of 35–39 kg m−2 and 6.36 (95% CI: 3.08–13.16) for BMI⩾40 kg m−2. Women with known diabetes at baseline were at three-fold higher risk (RR 3.13, 95% CI: 1.92–5.11) than those without diabetes; women who reported current smoking at baseline were at reduced risk compared to never smokers (RR 0.55, 95% CI: 0.35–0.86). The strong linear positive association of BMI with endometrial cancer risk and a strongly increased risk among women with diabetes suggest that any increase in body mass in the female population will increase endometrial cancer incidence.
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Deorukhkar A, Krishnan S, Sethi G, Aggarwal BB. Back to basics: how natural products can provide the basis for new therapeutics. Expert Opin Investig Drugs 2007; 16:1753-73. [PMID: 17970636 DOI: 10.1517/13543784.16.11.1753] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Phytochemicals have potent antitumor properties and have provided multiple active compounds in the past. Although there is an increasing focus on 'designer' targeted therapeutic anticancer agents, the broad spectrum of activity of natural products across multiple signaling pathways remains inadequately explored. The chemical diversity, structural complexity, affordability, lack of substantial toxic effects and inherent biologic activity of natural products makes them ideal candidates for new therapeutics. Natural products not only disrupt aberrant signaling pathways leading to cancer (i.e., proliferation, deregulation of apoptosis, angiogenesis, invasion and metastasis) but also synergize with chemotherapy and radiotherapy. This review focuses on the mechanism of action of key natural products and promising preclinical data on their efficacy as anticancer agents, as single agents and in combination with standard therapies.
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Affiliation(s)
- Amit Deorukhkar
- The University of Texas MD Anderson Cancer Center, Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
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28
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Venkata NG, Aung CS, Cabot PJ, Monteith GR, Roberts-Thomson SJ. PPARalpha and PPARbeta are differentially affected by ethanol and the ethanol metabolite acetaldehyde in the MCF-7 breast cancer cell line. Toxicol Sci 2007; 102:120-8. [PMID: 18003597 DOI: 10.1093/toxsci/kfm281] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The activity and/or the level of the peroxisome proliferator-activated receptors (PPARs) in liver and oligodendrocytes are regulated by ethanol. Despite the association between ethanol consumption and breast cancer risk, and the increasing evidence for an involvement of PPARs in some cancers, there have been no studies on the effect of ethanol or its metabolite acetaldehyde on PPARs in breast cancer. Using the MCF-7 breast cancer cell line, we examined the relationship between ethanol and its metabolite acetaldehyde on PPARalpha and PPARbeta transactivation. Ethanol (20 mM) reduced the potency of the PPARbeta ligand GW0742, evident by a rightward shift in the GW0742 dose-response curve, whereas for PPARalpha activation by GW7647, ethanol mediated its effects primarily through reducing efficacy as evidenced by a reduction in maximal response. Using the enzyme inhibitors 4-methylpyrazole and cyanamide and the metabolite acetaldehyde, we showed that PPARalpha and PPARbeta are differentially modulated by ethanol and acetaldehyde. While acetaldehyde is responsible for the inhibition of PPARalpha ligand inhibition with a concentration that inhibits 50% of activity (IC50) of 111 nM, acetaldehyde has no effect on PPARbeta or its ligand activation. Instead, inhibition of PPARbeta transactivation is mediated directly by ethanol. The differential effect of ethanol and acetaldehyde on PPARalpha and PPARbeta further underscores the differences between these receptors and may indicate the relevance of PPARs in the effects of ethanol in the human breast.
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Bocca C, Bozzo F, Francica S, Colombatto S, Miglietta A. Involvement of PPAR gamma and E-cadherin/beta-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells. Int J Cancer 2007; 121:248-56. [PMID: 17354222 DOI: 10.1002/ijc.22646] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPAR gamma is involved in growth inhibition of transformed cells. Ligands of PPAR gamma are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPAR gamma expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPAR gamma antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPAR gamma to levels up to control and caused PPAR gamma translocation into the nucleus. Furthermore, the overexpression of PPAR gamma positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the beta-catenin/E-cadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of beta-catenin and E-cadherin and the antagonist reverted only the effect on beta-catenin. These studies indicate that CLA regulates PPAR gamma expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells.
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Affiliation(s)
- Claudia Bocca
- Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy.
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Saidi SA, Holland CM, Charnock-Jones DS, Smith SK. In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Cancer 2006; 5:13. [PMID: 16569247 PMCID: PMC1475879 DOI: 10.1186/1476-4598-5-13] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2005] [Accepted: 03/28/2006] [Indexed: 11/23/2022] Open
Abstract
Fenofibrate, an agonist of PPAR-alpha, in doses above 25 μM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.
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Affiliation(s)
- Samir A Saidi
- University Department of Obstetrics & Gynaecology, The Rosie Hospital, Robinson Way, Cambridge, CB2 2SW, UK
| | - Cathrine M Holland
- University Department of Obstetrics & Gynaecology, The Rosie Hospital, Robinson Way, Cambridge, CB2 2SW, UK
| | - D Stephen Charnock-Jones
- University Department of Obstetrics & Gynaecology, The Rosie Hospital, Robinson Way, Cambridge, CB2 2SW, UK
| | - Stephen K Smith
- University Department of Obstetrics & Gynaecology, The Rosie Hospital, Robinson Way, Cambridge, CB2 2SW, UK
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Aung CS, Faddy HM, Lister EJ, Monteith GR, Roberts-Thomson SJ. Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation. Biochem Biophys Res Commun 2005; 340:656-60. [PMID: 16378595 DOI: 10.1016/j.bbrc.2005.12.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2005] [Accepted: 12/09/2005] [Indexed: 12/24/2022]
Abstract
To investigate the role of peroxisome proliferator-activated receptors (PPARs) alpha and beta in the differentiation of colon cancer cells, we differentiated HT-29 cells using sodium butyrate (NaB) and culturing post-confluence and assessed differentiation using the marker intestinal alkaline phosphatase. While PPARalpha levels only changed with culturing post confluence, PPARbeta levels increased independent of the method of differentiation. To explore further the differences induced by NaB, we assessed changes in both PPAR isoforms in MCF-7 breast cancer cells cultured in the presence of NaB over 48h. Again a very different expression pattern was observed with PPARalpha increasing after 4h and remaining elevated, while PPARbeta increased transiently. Our studies suggest that the expression of PPARs is dependent upon both the method of differentiation and on time. Moreover, these studies show that changes in PPARalpha levels are not required for the differentiation of colon cancer cell lines, whereas changes in PPARbeta are more closely associated with differentiation.
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Affiliation(s)
- Cho S Aung
- The School of Pharmacy, The University of Queensland, Brisbane, Qld 4072, Australia
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32
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence of HCC is rising worldwide, especially in the United States. The overall survival of patients with HCC is grim and currently no efficient secondary prevention or systemic treatments are available. Recent evidence suggests that COX-2 signaling is implicated in hepatocarcinogenesis and COX-2 inhibitors prevent HCC cell growth in vitro and in animal models. However, given the recently reported side effect associated with some of the COX-2 inhibitors, it is imperative to develop chemotherapeutic strategy that simultaneously targets COX-2 and other related key molecules in hepatocarcinogenesis or to utilize agents inhibiting COX-2 signaling in conjunction with other standard chemotherapy or radiation therapy. Such combinational therapeutic approaches are expected to provide synergistic anti-tumor effect with lesser side effect. In this regard, the recently delineated interplay between COX-2-derived PG signaling and other growth-regulatory pathways such as EGFR, Met, iNOS, VEGF and n-3 polyunsaturated fatty acids is expected to provide important therapeutic implications. This review summarizes the recent advances in understanding the mechanisms for COX-2-derived PG signaling in hepatocarcinogenesis and focuses on the newly unveiled interactions between PG cascade and other key signaling pathways that coordinately regulate HCC growth. Understanding these mechanisms and interplays will facilitate the development of more effective chemopreventive and therapeutic strategies.
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Affiliation(s)
- Tong Wu
- Department of Pathology, University of Pittsburgh School of Medicine, MUH E-740, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Shen WT, Chung WY. Treatment of thyroid cancer with histone deacetylase inhibitors and peroxisome proliferator-activated receptor-gamma agonists. Thyroid 2005; 15:594-9. [PMID: 16029127 DOI: 10.1089/thy.2005.15.594] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Among the most promising new antineoplastic therapies for poorly differentiated or undifferentiated thyroid cancer are the histone deacetylase inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma agonists. These two classes of drugs have been shown to inhibit growth and induce apoptosis and redifferentiation in a variety of hematologic and solid cancer cell lines and animal models. In this article we review the molecular mechanisms, in vitro and in vivo studies, and clinical applications of the histone deacetylase inhibitors and PPAR-gamma agonists in the treatment of thyroid cancer.
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Affiliation(s)
- Wen T Shen
- Department of Surgery, UCSF/Mt. Zion Medical Center, San Francisco, California, USA.
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Chen A, Xu J. Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol 2005; 288:G447-56. [PMID: 15486348 DOI: 10.1152/ajpgi.00209.2004] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related morbidity and mortality in the United States. Curcumin, the yellow pigment in turmeric, possesses inhibitory effects on growth of a variety of tumor cells by reducing cell proliferation and inducing apoptosis. Effects of the peroxisome proliferator-activated receptor-gamma (PPARgamma) on stimulating cell differentiation and on inducing cell cycle arrest have attracted attention from the perspective of treatment and prevention of cancer. The aim of this study was to elucidate the mechanisms by which curcumin inhibits colon cancer cell growth. In the present report, we observed that curcumin, in a dose-dependent manner, inhibited the growth of Moser cells, a human colon cancer-derived cell line, and stimulated the trans-activating activity of PPARgamma. Further studies demonstrated that activation of PPARgamma was required for curcumin to inhibit Moser cell growth. Activation of PPARgamma mediated curcumin suppression of the expression of cyclin D1, a critical protein in the cell cycle, in Moser cells. In addition, curcumin blocked EGF signaling by inhibiting EGF receptor (EGFR) tyrosine phosphorylation and suppressing the gene expression of EGFR mediated by activation of PPARgamma. In addition to curcumin reduction of the level of phosphorylated PPARgamma, inhibition of cyclin D1 expression played a major and significant role in curcumin stimulation of PPARgamma activity in Moser cells. Taken together, our results demonstrated for the first time that curcumin activation of PPARgamma inhibited Moser cell growth and mediated the suppression of the gene expression of cyclin D1 and EGFR. These results provided a novel insight into the roles and mechanisms of curcumin in inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.
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Affiliation(s)
- Anping Chen
- Department of Pathology, Louisiana State University, Health Sciences Center in Shreveport, 1501 Kings Hwy, Shreveport, LA 71130, USA.
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Ceni E, Mello T, Tarocchi M, Crabb DW, Caldini A, Invernizzi P, Surrenti C, Milani S, Galli A. Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells. World J Gastroenterol 2005; 11:1122-30. [PMID: 15754392 PMCID: PMC4250701 DOI: 10.3748/wjg.v11.i8.1122] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.
METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARγ was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARγ activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot.
RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate.
CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.
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Affiliation(s)
- Elisabetta Ceni
- Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgani 85, 50134 Firenze, Italy
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Lachal S, Ford J, Shulkes A, Baldwin GS. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells. ACTA ACUST UNITED AC 2005; 120:243-51. [PMID: 15177943 DOI: 10.1016/j.regpep.2004.03.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2003] [Revised: 03/15/2004] [Accepted: 03/26/2004] [Indexed: 02/08/2023]
Abstract
The three subtypes of peroxisome proliferator activated-receptors (PPARalpha, delta and gamma) control the storage and metabolism of fatty acids. Treatment of rats with the PPARalpha ligand ciprofibrate increases serum gastrin concentrations, and several lines of evidence suggest that non-amidated gastrins act as growth factors for the colonic mucosa. The aim of the present study was to investigate the expression of PPARs and the effect of PPAR ligands on gastrin production and cell proliferation in human colorectal carcinoma (CRC) cell lines. mRNAs for all three PPAR subtypes were detected by PCR in all CRC cell lines tested. The concentrations of progastrin, but not of glycine-extended or amidated gastrin, measured by radioimmunoassay in LIM 1899 conditioned media and cell extracts were significantly increased by treatment with the PPARalpha ligand clofibrate. Similar increases in progastrin were seen following treatment with the PPARalpha ligands ciprofibrate and fenofibrate, but not with bezafibrate, gemfibrozil or Wy 14643. The PPARgamma agonist rosiglitazone had no significant effect on progastrin production. The PPARalpha ligand clofibrate also stimulated proliferation of the LIM 1899 cell line. We conclude that some PPARalpha ligands increase progastrin production by the human CRC cell line LIM 1899, and that clofibrate increases proliferation of LIM 1899 cells. These studies have revealed a relationship between PPARs and gastrin, two regulatory molecules implicated in the pathogenesis of CRC.
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Affiliation(s)
- Shamilah Lachal
- Department of Surgery ARMC, University of Melbourne, Department of Surgery, Austin Health, Heidelberg, Victoria 3084, Australia
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Ibabe A, Bilbao E, Cajaraville MP. Expression of peroxisome proliferator-activated receptors in zebrafish (Danio rerio) depending on gender and developmental stage. Histochem Cell Biol 2004; 123:75-87. [PMID: 15616845 DOI: 10.1007/s00418-004-0737-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2004] [Indexed: 01/09/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors involved in embryo development and differentiation of several tissues in mammals. The aim of the present study was to investigate the possible differential expression of the three PPAR subtypes (PPARalpha, PPARbeta, and PPARgamma) in relation to gender and developmental stage in zebrafish. For this purpose PPAR expression was assessed by immunohistochemistry in 7-day-old larvae, 1-month-old juveniles, and 1-year-old adults. Additionally, the activity of peroxisomal acyl-CoA oxidase (AOX), a gene regulated by PPARs, and the volume density of catalase-immunolabeled liver peroxisomes (V(VP)) was examined. No significant gender-related differences were detected in the tissue distribution of the three PPAR subtypes or in peroxisomal AOX activity and V(VP). The percentage of PPARbeta-positive hepatocytes was significantly higher in females than in males suggesting a specific regulatory role of this subtype in female zebrafish. The three PPAR subtypes were already expressed at the larval stage, with a similar tissue distribution pattern to that found in adults. For all stages, PPARalpha and PPARgamma were expressed at higher levels than PPARbeta, and PPARbeta immunolabeling was stronger in juveniles than in larval or adult stages. The percentages of hepatocyte nuclei immunolabeled for PPARs was higher in early developmental stages than in adults, similarly to AOX activity and V(VP). In conclusion, our results indicate that PPAR expression, the activity of its target gene AOX, and peroxisomal biogenesis are developmentally modulated in zebrafish.
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Affiliation(s)
- Arantza Ibabe
- Biologia Zelularra eta Histologia Laborategia, Zoologia eta Animali Biologia Zelularra Saila, Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea/Universidad del País Vasco, 644 PK, 48080 Bilbo, Spain.
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Seargent JM, Yates EA, Gill JH. GW9662, a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation. Br J Pharmacol 2004; 143:933-7. [PMID: 15533890 PMCID: PMC1575954 DOI: 10.1038/sj.bjp.0705973] [Citation(s) in RCA: 155] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARgamma signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARgamma is observed in tumours compared to normal tissues and PPARgamma agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPARgamma antagonist GW9662 prevented activation of PPARgamma and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPARgamma activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPARgamma-independent pathways and question the central belief that PPARgamma ligands mediate their anticancer effects via activation of PPARgamma.
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Affiliation(s)
- Jill M Seargent
- Cancer Research Unit, Tom Connor's Cancer Research Centre, University of Bradford, All Saints Road, Bradford BD7 1DP
| | - Elisabeth A Yates
- Cancer Research Unit, Tom Connor's Cancer Research Centre, University of Bradford, All Saints Road, Bradford BD7 1DP
| | - Jason H Gill
- Cancer Research Unit, Tom Connor's Cancer Research Centre, University of Bradford, All Saints Road, Bradford BD7 1DP
- Author for correspondence:
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Abstract
Thyroid tumorigenesis and carcinogenesis accompany progressive loss of thyroid-specific differentiated functions. Some thyroid cancers are or become dedifferentiated, and they become refractory to efficacy-proven conventional therapies such as radioiodine ablation therapy and thyrotropin (TSH)-suppressive therapy. Redifferentiation therapy by either redifferentiating agents or gene transfer of differentiation-related genes may retard tumor growth and make tumors respond to conventional therapies.
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Affiliation(s)
- Jin-Woo Park
- Department of Surgery, College of Medicine, Chungbuk National University, San 62 Kaeshin-dong, Heungdok-gu, Cheongju, 361-763 South Korea
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Crowe DL, Chandraratna RAS. A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res 2004; 6:R546-55. [PMID: 15318936 PMCID: PMC549174 DOI: 10.1186/bcr913] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2003] [Revised: 06/15/2004] [Accepted: 06/24/2004] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Certain lipids have been shown to be ligands for a subgroup of the nuclear hormone receptor superfamily known as the peroxisome proliferator-activated receptors (PPARs). Ligands for these transcription factors have been used in experimental cancer therapies. PPARs heterodimerize and bind DNA with retinoid X receptors (RXRs), which have homology to other members of the nuclear receptor superfamily. Retinoids have been found to be effective in treating many types of cancer. However, many breast cancers become resistant to the chemotherapeutic effects of these drugs. Recently, RXR-selective ligands were discovered that inhibited proliferation of all-trans retinoic acid resistant breast cancer cells in vitro and caused regression of the disease in animal models. There are few published studies on the efficacy of combined therapy using PPAR and RXR ligands for breast cancer prevention or treatment. METHODS We determined the effects of selective PPAR and RXR ligands on established human breast cancer cell lines in vitro. RESULTS PPAR-alpha and PPAR-gamma ligands induced apoptotic and antiproliferative responses in human breast cancer cell lines, respectively, which were associated with specific changes in gene expression. These responses were potentiated by the RXR-selective ligand AGN194204. Interestingly, RXR-alpha-overexpressing retinoic acid resistant breast cancer cell lines were more sensitive to the effects of the RXR-selective compound. CONCLUSION RXR-selective retinoids can potentiate the antiproliferative and apoptotic responses of breast cancer cell lines to PPAR ligands.
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Affiliation(s)
- David L Crowe
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California, USA
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Melichar B, Konopleva M, Hu W, Melicharova K, Andreeff M, Freedman RS. Growth-inhibitory effect of a novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines not dependent on peroxisome proliferator-activated receptor-gamma expression. Gynecol Oncol 2004; 93:149-54. [PMID: 15047229 DOI: 10.1016/j.ygyno.2004.01.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2003] [Indexed: 10/26/2022]
Abstract
OBJECTIVES Despite the advent of new chemotherapeutic drugs in recent decades, epithelial ovarian carcinoma (EOC) remains the leading cause of death from gynecologic cancers, and new therapeutic targets and agents are urgently needed. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid with anti-tumor activity against a wide range of tumors in vitro and in vivo. CDDO is a ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of the present study was to evaluate CDDO activity in EOC cell lines in vitro. METHODS The expression of PPARgamma was examined by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in eight EOC cell lines (2774, SKOV3, CAOV3, OVCAR3, NMP-1, HEY, 2008 and 2008.C13), and the growth inhibitory activity of CDDO was assessed using the MTT assay. RESULTS PPARgamma RNA was expressed in all eight cell lines examined, but the expression varied widely among cell lines. In contrast, CDDO showed a similar degree of activity in different EOC cell lines independent of cisplatin sensitivity, with 50% inhibitory concentrations ranging from 1 to 4 microM. Experiments combining CDDO with cisplatin and paclitaxel indicated weak antagonism. The growth-inhibitory activity of CDDO was unaffected by PPARgamma antagonist T007. CONCLUSIONS Although differences were observed in PPARgamma expression in EOC cell lines, CDDO had similar growth-inhibitory activity in all cell lines examined, indicating that the antitumor activity of CDDO in vitro is mediated by a mechanism independent of PPARgamma. The activity of CDDO in platinum-resistant cell lines is encouraging with respect to the potential clinical use of the drug.
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Affiliation(s)
- Bohuslav Melichar
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Tien ES, Davis JW, Vanden Heuvel JP. Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. J Biol Chem 2004; 279:24053-63. [PMID: 15051727 DOI: 10.1074/jbc.m401489200] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Like other nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) use a wide variety of protein-protein interactions to properly regulate transcription of target genes. In an attempt to identify novel PPAR-interacting proteins, a cDNA expression library was screened with bacterially expressed PPARalpha. One of the genes identified as a PPARalpha-associated protein by interaction cloning was the CREB-binding protein/p300-interacting transactivator with ED-rich tail 2 (CITED2, also called p35srj/mrg1/msg1). This coactivator interacted directly with PPARalpha in the presence or absence of ligand predominantly via the ligand binding domain of the nuclear receptor. In transient transfection reporter assays, CITED2 acted as a dose-dependent coactivator of PPARalpha-dependent transcriptional regulation in the presence of several exogenous ligands. CITED2 also increased PPARgamma-dependent regulation of reporter genes but had no effect on PPARbeta activity. To determine whether CITED2 affects endogenous gene expression, this protein was stably overexpressed (CITED2+) or repressed by small inhibitor RNA (CITED2-) in immortalized mouse hepatocytes. Relative to the control stably transfected or CITED2-cells, CITED2+ cells had an increased rate of cell proliferation. Microarray analysis and real time PCR showed that several genes are differentially affected by PPARalpha ligands in CITED2+ versus CITED2-cells. Genes that were affected by PPARalpha ligands in a CITED2-modulatory manner include angiopoietin-like protein 4, forkhead C2, hypoxia-inducible factor-1alpha, and MAPK phosphatase 1. Interestingly these genes share common functions in that they are known to promote vascularization and angiogenesis in response to hypoxia. The results described here suggest that CIT-ED2 is a coactivator of PPARalpha and that both proteins may participate in signaling cascades of hypoxic response and angiogenesis.
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Affiliation(s)
- Eric S Tien
- Center for Molecular Toxicology and Carcinogenesis and Department of Veterinary Science, Pennsylvania State University, University Park, Pennsylvania 16802, USA
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Vosper H, Khoudoli GA, Palmer CNA. The peroxisome proliferator activated receptor δ is required for the differentiation of THP-1 monocytic cells by phorbol ester. NUCLEAR RECEPTOR 2003; 1:9. [PMID: 14670086 PMCID: PMC317379 DOI: 10.1186/1478-1336-1-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2003] [Accepted: 12/11/2003] [Indexed: 01/30/2023]
Abstract
Background PPARδ (NR1C2) promotes lipid accumulation in human macrophages in vitro and has been implicated in the response of macrophages to vLDL. We have investigated the role of PPARδ in PMA-stimulated macrophage differentiation. The THP-1 monocytic cell line which displays macrophage like differentiation in response to phorbol esters was used as a model system. We manipulated the response to PMA using a potent synthetic agonist of PPARδ , compound F. THP-1 sub-lines that either over-expressed PPARδ protein, or expressed PPARδ anti-sense RNA were generated. We then explored the effects of these genetic modulations on the differentiation process. Results The PPARδ agonist, compound F, stimulated differentiation in the presence of sub-nanomolar concentrations of phorbol ester. Several markers of differentiation were induced by compound F in a synergistic fashion with phorbol ester, including CD68 and IL8. Over-expression of PPARδ also sensitised THP-1 cells to phorbol ester and correspondingly, inhibition of PPARδ by anti-sense RNA completely abolished this response. Conclusions These data collectively demonstrate that PPARδ plays a fundamental role in mediating a subset of cellular effects of phorbol ester and supports observations from mouse knockout models that PPARδ is involved in macrophage-mediated inflammatory responses.
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Affiliation(s)
- Helen Vosper
- Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK
| | - Guennadi A Khoudoli
- Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK
- Medical Sciences Institute, University of Dundee, Nethergate, Dundee. DD1 4HN, UK
| | - Colin NA Palmer
- Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK
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Bishop-Bailey D, Wray J. Peroxisome proliferator-activated receptors: a critical review on endogenous pathways for ligand generation. Prostaglandins Other Lipid Mediat 2003; 71:1-22. [PMID: 12749590 DOI: 10.1016/s0090-6980(03)00003-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Lipid mediators can exert their effects by interactions with well-characterised cell surface G-protein-linked receptors. Recently, a group of intracellular receptors have been identified that are activated by a large variety of lipid-derived mediators. Amongst these novel targets, the peroxisome proliferator-activated receptors (PPARs), a family of three (PPARalpha, beta/delta and gamma) nuclear receptor/transcription factors have become a major area for investigation. PPARs are found throughout the body, where they have diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. There is a great interest, therefore, in the roles of PPARs in a variety of pathological conditions, including diabetes, atherosclerosis, cancer and chronic inflammation. Although, a number of naturally occurring compounds can activate PPARs, it has been difficult, as yet, to characterise any of these mediators as truly endogenous ligands. These findings have lead to the suggestion that PPARs may act just as general lipid sensors. Acting as lipid sensors, PPARs may take changes in lipid/fatty acid balance in the diet or local metabolism and translate them to tissue-specific ligands, exerting tissue-specific effects. Using classical pharmacological criteria for endogenous mediator classification we will critically discuss the variety of pathways for putative ligand generation.
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Affiliation(s)
- David Bishop-Bailey
- Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Barts, UK.
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Ehrmann J, Vavrusová N, Collan Y, Kolár Z. Peroxisome proliferator-activated receptors (PPARs) in health and disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2002; 146:11-4. [PMID: 12572888 DOI: 10.5507/bp.2002.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of steroid-thyroid-retinoid nuclear receptors. PPARs are transcription factors activated by specific ligands and play an important role during cell signalling. Intensive study of PPARs during recent years has revealed their importance in both normal physiology and in the pathology of various tissues. They participate in the regulation of lipid metabolism, inflammation and the development of atherosclerosis or diabetes. They also play a role in the regulation of growth and differentiation of cancer. It has been suggested that PPAR ligands may have potent anticancer effects and therefore may serve as potential anticancer drugs. In this review we focus on a role of PPARs in breast cancer and in glial tumors of the brain.
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Affiliation(s)
- Jirí Ehrmann
- Department of Pathology, Laboratory of Molecular Pathology, Faculty of Medicine, Palacký University, Hnevotínská 3, Olomouc 77515, Czech Republic.
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Suchanek KM, May FJ, Robinson JA, Lee WJ, Holman NA, Monteith GR, Roberts-Thomson SJ. Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231. Mol Carcinog 2002; 34:165-71. [PMID: 12203367 DOI: 10.1002/mc.10061] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor (PPAR) alpha is a ligand-activated transcription factor that has been linked with rodent hepatocarcinogenesis. It has been suggested that PPARalpha mRNA expression levels are an important determinant of rodent hepatic tumorigenicity. Previous work in rat mammary gland epithelial cells showed significantly increased PPARalpha mRNA expression in carcinomas, suggesting the possible role of this isoform in rodent mammary gland carcinogenesis. In this study we sought to determine whether PPARalpha is expressed and dynamically regulated in human breast cancer MCF-7 and MDA-MB-231 cells. Having established the presence of PPARalpha in both cell types, we then examined the consequence of PPARalpha activation, by its ligands Wy-14,643 and clofibrate, on proliferation. With real-time reverse transcriptase-polymerase chain reaction, we showed that PPARalpha mRNA was dynamically regulated in MDA-MB-231 cells and that PPARalpha activation significantly increased proliferation of the cell line. In contrast, PPARalpha expression in MCF-7 cells did not change with proliferation during culture and was present at significantly lower levels than in MDA-MB-231 cells. However, PPARalpha ligand activation still significantly increased the proliferation of MCF-7 cells. The promotion of proliferation in breast cancer cell lines following PPARalpha activation was in stark contrast to the effects of PPARgamma-activating ligands that decrease proliferation in human breast cancer cells. Our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. Hence, this pathway may be significant in mammary gland tumorigenesis.
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Affiliation(s)
- Kate M Suchanek
- School of Pharmacy, University of Queensland, St. Lucia, Australia
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Oliver JD, Roberts RA. Receptor-mediated hepatocarcinogenesis: role of hepatocyte proliferation and apoptosis. PHARMACOLOGY & TOXICOLOGY 2002; 91:1-7. [PMID: 12193254 DOI: 10.1034/j.1600-0773.2002.910101.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The rodent liver is a target organ for the action of several non-genotoxic carcinogens. These include dioxins, polychlorinated biphenyls, phenobarbital, peroxisome proliferators and organochlorine pesticides. These chemicals disrupt the homeostasis of the liver by perturbing hepatocyte cell death and proliferation, causing hyperplasia leading to tumour formation. Significant progress has been made towards elucidating the mechanisms of action of these toxicants since the discovery of receptors that bind specific classes of xenobiotics. Dioxins and polychlorinated biphenyls bind to the aryl hydrocarbon receptor, phenobarbital binds to the constitutive androstane receptor and peroxisome proliferators act via the their activated receptor alpha. These three receptors have ligand-dependent transcription activities and therefore mediate changes in gene expression in response to toxicant exposure. The development of transgenic mouse strains where the genes for these receptors are disrupted has demonstrated that receptor activity is essential for the toxicity of these carcinogens. This implies that changes in the expression of key target genes control proliferation and apoptosis in the xenobiotic-induced hepatocyte phenotype.
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Affiliation(s)
- Jason D Oliver
- Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK.
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Ge R, Tao L, Kramer PM, Cunningham ML, Pereira MA. Effect of peroxisome proliferators on the methylation and protein level of the c-myc protooncogene in B6C3F1 mice liver. J Biochem Mol Toxicol 2002; 16:41-7. [PMID: 11857776 DOI: 10.1002/jbt.10019] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Peroxisome proliferators in general are nongenotoxic mouse liver carcinogens for which DNA hypomethylation and altered gene expression are proposed mechanisms. Therefore, the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D), dibutyl phthalate (DBP), gemfibrozil, and Wy-14,643 were evaluated for the ability to alter the methylation and expression of the c-myc protooncogene. Male B6C3F1 mice were administered for 6 days in their diet Wy-14,643 (5-500 ppm), 2,4-D (1,680 ppm), DBP (20,000 ppm), or gemfibrozil (8,000 ppm). All four peroxisome proliferators caused hypomethylation of the c-myc gene in the liver. Wy-14,643 appeared to be the most efficacious with a threshold between 10 and 50 ppm. The level of the c-myc protein was increased by Wy-14,643, but not the other peroxisome proliferators. When female B6C3F1 mice received a two-thirds partially hepatectomy and 16 h later were administered 50 mg/kg Wy-14,643 by gavage, hypomethylation of the gene occurred 24 h later. Hypomethylation was not found in mice that received Wy-14,643 following a sham operation. Hypomethylation of the c-myc gene within 24 h of administering Wy-14,643 after a partial hepatectomy but not after a sham operation supports the hypothesis that the peroxisome proliferators prevent methylation of hemimethylated sites formed by DNA replication.
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Affiliation(s)
- Rongrong Ge
- Department of Pathology, Medical College of Ohio, Toledo, OH 43614-5806, USA
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Rossi GP, Seccia TM, Nussdorfer GG. Reciprocal regulation of endothelin-1 and nitric oxide: relevance in the physiology and pathology of the cardiovascular system. INTERNATIONAL REVIEW OF CYTOLOGY 2002; 209:241-72. [PMID: 11580202 DOI: 10.1016/s0074-7696(01)09014-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The endothelium plays a crucial role in the regulation of cardiovascular structure and function by releasing several mediators in response to biochemical and physical stimuli. These mediators are grouped into two classes: (1) endothelium-derived constricting factors (EDCFs) and (2) endothelium-derived relaxing factors (EDRFs), the roles of which are considered to be detrimental and beneficial, respectively. Endothelin-1 (ET-1) and nitric oxide (NO) are the prototypes of EDCFs and EDRFs, respectively, and their effects on the cardiovascular system have been studied in depth. Numerous conditions characterized by an impaired availability of NO have been found to be associated with enhanced synthesis of ET-1, and vice versa, thereby suggesting that these two factors have a reciprocal regulation. Experimental studies have provided evidence that ET-1 may exert a bidirectional effect by either enhancing NO production via ETB receptors located in endothelial cells or blunting it via ETA receptors prevalently located in the vascular smooth muscle cells. Conversely, NO was found to inhibit ET-1 synthesis in different cell types. In vitro and in vivo studies have started to unravel the molecular mechanisms involved in this complex interaction. It has been clarified that several factors affect in opposite directions the transcription of preproET-1 and NO-synthase genes, nuclear factor-KB and peroxisome proliferator-activated receptors playing a key role in these regulatory mechanisms. ET-1 and NO interplay seems to have a great relevance in the physiological regulation of vascular tone and blood pressure, as well as in vascular remodeling. Moreover, an imbalance between ET-1 and NO systems may underly the mechanisms involved in the pathogenesis of systemic and pulmonary hypertension and atherosclerosis.
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Affiliation(s)
- G P Rossi
- Department of Clinical and Experimental Medicine, University Hospital, University of Padua, Italy
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