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Kamposioras K, Dinas PC, Barriuoso J, Trachana V, Dimas K. Caveolin-1 protein expression as a prognostic biomarker of gastrointestinal tumours: A systematic review and meta-analysis. Eur J Clin Invest 2023; 53:e14065. [PMID: 37497737 DOI: 10.1111/eci.14065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/02/2023] [Accepted: 07/08/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Gastrointestinal (GI) cancers remain a major threat worldwide, accounting for over 30% of cancer deaths. The identification of novel prognostic biomarkers remains a challenge despite significant advances in the field. The CAV1 gene, encoding the caveolin-1 protein, remains enigmatic in cancer and carcinogenesis, as it has been proposed to act as both a tumour promoter and a tumour suppressor. METHODS To analyse the differential role of caveolin-1 expression in both tumour cells and stroma in relation to prognosis in GI tumours, we performed a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; PROSPERO registration number: CRD42022299148. RESULTS Our analysis showed that high levels of caveolin-1 in tumour cells were associated with poor prognosis and inferior overall survival (OS) in oesophageal and pancreatic cancer and hepatocellular carcinoma (HCC), but not in gastric and colorectal cancer. Importantly, our study showed that higher stromal caveolin-1 expression was associated with significantly longer OS and disease-free survival in colorectal cancer. Analysis of stromal caveolin-1 expression in the remaining tumours showed a similar trend, although it did not reach statistical significance. CONCLUSIONS The data suggest that caveolin-1 expression in the tumour cells of oesophageal, pancreatic cancer and HCC and in the stroma of colorectal cancer may be an important novel predictive biomarker for the clinical management of these diseases in a curative setting. However, the main conclusion of our analysis is that caveolin-1 expression should always be assessed separately in stroma and tumour cells.
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Affiliation(s)
| | - Petros C Dinas
- FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Volos, Greece
| | - Jorge Barriuoso
- The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Volos, Greece
| | - Konstantinos Dimas
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Volos, Greece
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Delmas D, Cotte AK, Connat JL, Hermetet F, Bouyer F, Aires V. Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses. Cancers (Basel) 2023; 15:4100. [PMID: 37627128 PMCID: PMC10452604 DOI: 10.3390/cancers15164100] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance.
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Affiliation(s)
- Dominique Delmas
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
- Centre de Lutte Contre le Cancer Georges François Leclerc, 21000 Dijon, France
| | - Alexia K. Cotte
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Jean-Louis Connat
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - François Hermetet
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Florence Bouyer
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Virginie Aires
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
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Han L, Huang Q, Yang J, Lu W, Hu M, Yang Y, Zhu H, Pang K, Yang G. Proteomic analysis of milk fat globule membranes from small-sized milk fat globules and their function in promoting lipid droplet fusion in bovine mammary epithelial cells. Food Funct 2023; 14:2304-2312. [PMID: 36752527 DOI: 10.1039/d2fo03476j] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In mammary epithelial cells, milk fat is synthesized as lipid droplets and secreted in the form of globules. Milk fat globules (MFGs) are covered by a lipid-protein membrane known as the milk fat globule membrane (MFGM). We randomly divided 12 Holstein cows into control and conjugated linoleic acid (CLA) groups. The control group was fed a basal diet, while the CLA group was fed the basal diet + CLA (15 g per kg DM) for 10 days. Cow performance, milk composition, and MFG size were measured daily. On day 10, we extracted MFGM proteins (n = 3) and identified them via quantitative proteomic analysis. We investigated the effects of the MFGM proteins from control and CLA-treated milk on the lipid droplet formation in MAC-T cells. Compared with the control group, the CLA group had reduced milk fat content (3.39 g/100 mL vs. 2.45 g/100 mL) and MFG size parameters (D[4,3] of 3.85 μm vs. 3.37 μm; D[3,2] of 3.24 μm vs. 2.83 μm). The specific surface area (SSA) increased in the CLA group. A total of 361 differentially expressed proteins were identified in the CLA group by iTRAQ quantitative proteomic analysis. Among these proteins, 100 were upregulated and 251 were downregulated (p < 0.05). In MAC-T cells, CLA-MFGM proteins increased the diameter of the lipid droplets to 1.32 μm. CLA-MFGM proteins decreased the proportion of the small lipid droplets (15.33% vs. 47.78%) and increased the proportion of the large lipid droplets (25.04% vs. 11.65%). CLA-MFGM proteins promoted lipid droplet fusion. Therefore, MFGM proteins play an important role in the regulation of the lipid droplet size.
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Affiliation(s)
- Liqiang Han
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Qixue Huang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - JingNa Yang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Wenyan Lu
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Mingyue Hu
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Yanbin Yang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Heshui Zhu
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, P. R. China.
| | - Kun Pang
- College of Animal Science and Veterinary Medicine, Xinyang Agriculture and Forestry University, Xinyang 464399, P. R. China
| | - Guoyu Yang
- College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, P. R. China
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Gorospe B, Moura JJG, Gutierrez-Merino C, Samhan-Arias AK. Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1-42) Interactions with Calmodulin and Calbindin-D28k. Int J Mol Sci 2022; 23:2289. [PMID: 35216403 PMCID: PMC9736327 DOI: 10.3390/ijms232315203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 12/12/2022] Open
Abstract
Amyloid β1-42 (Aβ(1-42)) oligomers have been linked to the pathogenesis of Alzheimer's disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1-42) oligomers and extensively binds internalized Aβ(1-42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1-42), using a combined strategy based on the experimental results obtained for Aβ(1-42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1-42) HiLyteTM-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1-42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1-42):CaM and of Aβ(1-42):calbindin-D28k complexes.
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Affiliation(s)
- Berta Gorospe
- LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Lisbon, Portugal
| | - José J. G. Moura
- LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Lisbon, Portugal
| | - Carlos Gutierrez-Merino
- Research Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
| | - Alejandro K. Samhan-Arias
- LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Lisbon, Portugal
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
- Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
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Gokani S, Bhatt LK. Caveolin-1: A promising therapeutic target for diverse diseases. Curr Mol Pharmacol 2021; 15:701-715. [PMID: 34847854 DOI: 10.2174/1874467214666211130155902] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/26/2021] [Accepted: 05/24/2021] [Indexed: 11/22/2022]
Abstract
The plasma membrane of eukaryotic cells contains small flask-shaped invaginations known as caveolae that are involved in the regulation of cellular signaling. Caveolin-1 is a 21-24kDa protein localized in the caveolar membrane. Caveolin-1 (Cav-1) has been considered as a master regulator among the various signaling molecules. It has been emerging as a chief protein regulating cellular events associated with homeostasis, caveolae formation, and caveolae trafficking. In addition to the physiological role of cav-1, it has a complex role in the progression of various diseases. Caveolin-1 has been identified as a prognosticator in patients with cancer and has a dual role in tumorigenesis. The expression of Cav-1 in hippocampal neurons and synapses is related to neurodegeneration, cognitive decline, and aging. Despite the ubiquitous association of caveolin-1 in various pathological processes, the mechanisms associated with these events are still unclear. Caveolin-1 has a significant role in various events of the viral cycle, such as viral entry. This review will summarize the role of cav-1 in the development of cancer, neurodegeneration, glaucoma, cardiovascular diseases, and infectious diseases. The therapeutic perspectives involving clinical applications of Caveolin-1 have also been discussed. The understanding of the involvement of caveolin-1 in various diseased states provides insights into how it can be explored as a novel therapeutic target.
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Affiliation(s)
- Shivani Gokani
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai. India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai. India
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Malikova E, Kmecova Z, Doka G, Pivackova LB, Balis P, Trubacova S, Velasova E, Krenek P, Klimas J. Pioglitazone restores phosphorylation of downregulated caveolin-1 in right ventricle of monocrotaline-induced pulmonary hypertension. Clin Exp Hypertens 2021; 44:101-112. [PMID: 34747283 DOI: 10.1080/10641963.2021.1996589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Caveolin-1 (cav-1) plays a role in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH is characterized by a loss of cav-1 in pulmonary arteries; however, less is known regarding its role in the hypertrophied right ventricle (RV). We aimed to characterize the role of cav-1 and Hsp90 in the RV of MCT-induced PAH and their impact on endothelial nitric oxide synthase (eNOS). Additionally, we focused on restoration of cav-1 expression with pioglitazone administration. METHODS Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). Selected proteins (cav-1, eNOS, pSer1177eNOS, Hsp90) and mRNAs (cav-1α, cav-1β, eNOS) were determined in the RV and left ventricle (LV) 4 weeks later. In a separate MCT-induced PAH study, pioglitazone (10 mg/kg/d, orally) administration started on day 14 after MCT. RESULTS MCT induced RV hypertrophy and lung enlargement. Cav-1 and pTyr14cav-1 were decreased in RV. Caveolin-1α (cav-1α) and caveolin-1β (cav-1β) mRNAs were decreased in both ventricles. Hsp90 protein was increased in RV. eNOS and pSer1177eNOS proteins were unchanged in the ventricles. eNOS mRNA was reduced in RV. Pioglitazone treatment increased oxygen saturation and pTyr14cav-1 vs. MCT group. CONCLUSIONS Restoration of pTyr14cav-1 did not lead to amelioration of the disease, nor did it prevent RV hypertrophy and fibrosis, which was indicated by an increase in Acta2, Nppb, Col3a1, and Tgfβ1 mRNA.
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Affiliation(s)
- Eva Malikova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Zuzana Kmecova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Gabriel Doka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Lenka Bies Pivackova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Peter Balis
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, Bratislava, Slovakia
| | - Simona Trubacova
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Eva Velasova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Peter Krenek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
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Kamposioras K, Vassilakopoulou M, Anthoney A, Bariuoso J, Mauri D, Mansoor W, Papadopoulos V, Dimas K. Prognostic significance and therapeutic implications of Caveolin-1 in gastrointestinal tract malignancies. Pharmacol Ther 2021; 233:108028. [PMID: 34755606 DOI: 10.1016/j.pharmthera.2021.108028] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2021] [Indexed: 02/07/2023]
Abstract
Caveolin-1 (CAV1) is expressed in several solid tumors both in cancerous cells as well as in tumor stroma and is reported to be related to cancer progression, metastasis, therapy resistance and clinical outcomes. Many studies report contrasting functions of this protein depending on the tumor cell model, the tumor type, or the stage of cancer studied. This protein is reported to function both as tumor suppressor and as tumor promoter. In this review, we aim to summarize translational and clinical studies that provide evidence of the role of CAV1 in tumor progression and survival outcome focusing on tumors of the gastrointestinal (GI) tract. Towards this aim, a detailed search has been performed for studies on the expression and the role of CAV1 in oesophageal, gastric, colorectal, pancreatic cancer and cholangiocarcinoma prognosis. We also review and discuss the implication of CAV1 in the outcome of pharmacological interventions. We conclude that CAV1 has the potential to become an important prognostic, and possibly predictive, biomarker in GI malignancies. It may also become a novel target towards the development of improved cancer therapies. However, it is obvious that there remains a lack of consensus on important issues such as the methodologies and cut-off levels in caveolin assessment. This ultimately result in many studies being contradictory not only in terms of the role of CAV1 as a tumor-promoting or suppressing gene but also in terms of the tumor compartment in which the levels of this protein may be of clinical significance. Addressing these important technical issues, in conjunction with a further elucidation of the role of CAV1 in tumor formation and progression, will delineate the importance of CAV1 in prognostic and therapeutic perspectives.
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Affiliation(s)
| | - Maria Vassilakopoulou
- Department of Medical Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Alan Anthoney
- Leeds Institute of Medical Research at St James' Hospital, University of Leeds, Leeds, UK
| | - Jorge Bariuoso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK; Manchester Cancer Research Centre, UK
| | - Davide Mauri
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Was Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Vassilios Papadopoulos
- Department of Medical Oncology, University Hospital of Larissa, University of Thessaly, Greece
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Zhao Y, Wei X, Song J, Zhang M, Huang T, Qin J. Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Protects Blood-Brain Barrier Integrity Following Diffuse Axonal Injury by Decreasing the Levels of Inflammatory Mediators Through a Caveolin-1-Dependent Pathway. Inflammation 2019; 42:841-856. [PMID: 30488141 DOI: 10.1007/s10753-018-0940-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Our early experiments confirmed that rosiglitazone (RSG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, had therapeutic potential for the treatment of diffuse axonal injury (DAI) by inhibiting the expression of amyloid-beta precursor protein and reducing the loss and abnormal phosphorylation of tau, but the underlying mechanisms were not fully defined. In this study, we aimed to investigate a possible role for PPARγ in the protection of blood-brain barrier (BBB) integrity in a rat model of DAI, and the underlying mechanisms. PPAR agonists and antagonists were intraperitoneally injected after DAI. Treatment with RSG ameliorated axonal injury, cell apoptosis, glia activation, and the release of inflammatory factors such as TNF-α, IL-1β, and IL-6. It also increased the expression of tight junction-associated proteins like ZO-1, claudin-5, and occludin-1, whereas the PPARγ antagonist GW9662 had the opposite effects. These effects were also studied in a BBB in vitro model, consisting of a monolayer of human microvascular endothelial cells (HBMECs) subjected to oxygen and glucose deprivation (OGD). Treatment with RSG ameliorated the loss of BBB integrity and the increased permeability induced by OGD by reducing the release of inflammatory factors and maintaining the expression of tight junction-associated proteins. Interestingly, caveolin-1 was found located mainly in endothelial cells, and RSG increased the expression of caveolin-1, which decreased following OGD. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model. In conclusion, we provide evidence that PPARγ plays an important role in a series of processes associated with DAI, and that the PPARγ agonist RSG can protect BBB integrity by decreasing the levels of inflammatory mediators through a caveolin-1-dependent pathway.
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Affiliation(s)
- Yonglin Zhao
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Xing Wei
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jinning Song
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ming Zhang
- Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Tingqin Huang
- Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jie Qin
- Department of Orthopedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, People's Republic of China.
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Liu B, Zheng T, Dong L, Mao C, Xu C, Mou X, Luo X, Lu Q, Dong X, Liu J, Kang P, Ding C, Xiao Y, Jiang P. Caveolin-1 Regulates CCL5 and PPARγ Expression in Nthy-ori 3-1 Cells: Possible Involvement of Caveolin-1 and CCL5 in the Pathogenesis of Hashimoto's Thyroiditis. Endocr Metab Immune Disord Drug Targets 2019; 20:609-618. [PMID: 31789139 DOI: 10.2174/1871530319666191202115149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 09/09/2019] [Accepted: 10/12/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hashimoto's thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid parenchyma, which ultimately leads to tissue destruction and loss of function. Caveolin-1 (Cav-1) is an essential structural constituent of lipid rafts in the plasma membrane of cells and is reported to be significantly reduced in thyrocytes from HT patients. However, the mechanism of Cav-1 involvement in HT pathogenesis is still largely unclear. METHODS Cav-1 expression in thyroid tissues from HT patients and euthyroid nodular goiter tissues was detected by immunohistochemistry staining. Cav-1 knockdown and overexpression were constructed by lentiviral transfection in the human thyroid follicular epithelial cell (TFC) line of Nthy-ori 3-1. The mRNA expression levels of chemokines in TFCs were determined by quantitative real-time PCR (qPCR). Cav-1 and peroxisome proliferator-activated receptor gamma (PPARγ) levels were analysed by qPCR and Western blot analysis. The migration ability of peripheral blood mononuclear cells (PBMCs) was detected by the Transwell assay. RESULTS In this study, Cav-1 and PPARγ expression was reduced in the thyroid tissues from HT patients. In vitro experiments showed that the expressions of chemokine (C-C motif) ligand 5 (CCL5) and migration of PBMCs were markedly increased, while the level of PPARγ was significantly decreased after the lentivirus-mediated knockdown of Cav-1 in Nthy-ori 3-1 cells. Interestingly, pioglitazone, a PPARγ agonist, not only upregulated PPARγ and Cav-1 proteins significantly, but also effectively reversed the Cav-1-knockdown-induced upregulation of CCL5 in Nthy-ori 3-1 cells and reduced the infiltration of lymphocytes. CONCLUSION The inhibition of Cav-1 upregulated the CCL5 expression and downregulated the PPARγ expression in TFC while pioglitazone, a PPARγ agonist, reversed the detrimental consequence. This outcome might be a potential target for the treatment of lymphocyte infiltration into the thyroid gland and HT development.
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Affiliation(s)
- Baocui Liu
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.,Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Tingting Zheng
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Liyang Dong
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chaoming Mao
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chengcheng Xu
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiao Mou
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xuan Luo
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Qingyan Lu
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xin Dong
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jiameng Liu
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ping Kang
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chao Ding
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yichuan Xiao
- Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Peng Jiang
- Department of Anesthesiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Sun L, Bian K. The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II. Int J Biol Sci 2019; 15:1215-1224. [PMID: 31223281 PMCID: PMC6567814 DOI: 10.7150/ijbs.29741] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 03/12/2019] [Indexed: 12/24/2022] Open
Abstract
Evidence has documented local angiotensin II (Ang II) as a pro-oxidant and pro-inflammatory molecule contributes to progressive deterioration of organ function in diseases. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, plays crucial roles in protection against oxidative stress and inflammation. Ang II stimulation decreases PPARγ protein in multiple types of cells, while the regulatory role of Ang II on PPARγ is not clear. Here we show that Ang II down-regulated PPARγ in ECV304 cells through 2 actions, inducing nuclear export and loss of protein. The nuclear export of PPARγ occurred transiently in the early phase, while the reduction in PPARγ protein happened in the later phase and was more persistent. Both alterations in PPARγ were accompanied by the decrease in PPARγ-DNA binding activity. Reduction of PPARγ protein levels was also coupled with the inhibition of PPARγ target genes. In addition, activation of PPARγ by its ligand troglitazone could completely counteract both 2 actions of Ang II on PPARγ. Further studies demonstrated that the decline of PPARγ protein was in association with ubiquitin-proteasome-dependent degradation, which was supported by the increase in polyubiquitin-PPARγ conjugates and the inhibitory effect of lactacystin, a specific proteasome inhibitor, on the loss of PPARγ. Taken together, this study uncovers a novel means by which Ang II down-regulates PPARγ. This down-regulation disrupts nuclear PPARγ function, which may lead to the loss of beneficial effects of PPARγ in response to Ang II stress.
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Affiliation(s)
- Li Sun
- Tianjin Medical University General Hospital; Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, PR China.,Murad Research Institute for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China
| | - Ka Bian
- Department of Biochemistry and Molecular Medicine, The George Washington University, Ross Hall 2300 Eye Street, NW, Washington, DC 20037, USA
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11
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Morén B, Hansson B, Negoita F, Fryklund C, Lundmark R, Göransson O, Stenkula KG. EHD2 regulates adipocyte function and is enriched at cell surface-associated lipid droplets in primary human adipocytes. Mol Biol Cell 2019; 30:1147-1159. [PMID: 30811273 PMCID: PMC6724522 DOI: 10.1091/mbc.e18-10-0680] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Adipocytes play a central role in energy balance, and dysfunctional adipose tissue severely affects systemic energy homeostasis. The ATPase EH domain–containing 2 (EHD2) has previously been shown to regulate caveolae, plasma membrane-specific domains that are involved in lipid uptake and signal transduction. Here, we investigated the role of EHD2 in adipocyte function. We demonstrate that EHD2 protein expression is highly up-regulated at the onset of triglyceride accumulation during adipocyte differentiation. Small interfering RNA–mediated EHD2 silencing affected the differentiation process and impaired insulin sensitivity, lipid storage capacity, and lipolysis. Fluorescence imaging revealed localization of EHD2 to caveolae, close to cell surface–associated lipid droplets in primary human adipocytes. These lipid droplets stained positive for glycerol transporter aquaporin 7 and phosphorylated perilipin-1 following adrenergic stimulation. Further, EHD2 overexpression in human adipocytes increased the lipolytic signaling and suppressed the activity of transcription factor PPARγ. Overall, these data suggest that EHD2 plays a key role for adipocyte function.
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Affiliation(s)
- Björn Morén
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
| | - Björn Hansson
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
| | - Florentina Negoita
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
| | - Claes Fryklund
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
| | - Richard Lundmark
- Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden
| | - Olga Göransson
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
| | - Karin G Stenkula
- Department of Experimental Medical Science, Lund University, 223 84 Lund, Sweden
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12
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Yang K, Zhao M, Huang J, Zhang C, Zheng Q, Chen Y, Jiang H, Lu W, Wang J. Pharmacological activation of PPARγ inhibits hypoxia-induced proliferation through a caveolin-1-targeted and -dependent mechanism in PASMCs. Am J Physiol Cell Physiol 2018; 314:C428-C438. [PMID: 29351409 DOI: 10.1152/ajpcell.00143.2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Previously, we and others have demonstrated that activation of peroxisome proliferator-activated receptor γ (PPARγ) by specific pharmacological agonists inhibits the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH) by suppressing the proliferation and migration in distal pulmonary arterial smooth muscle cells (PASMCs). Moreover, these beneficial effects of PPARγ are mediated by targeting the intracellular calcium homeostasis and store-operated calcium channel (SOCC) proteins, including the main caveolae component caveolin-1. However, other than the caveolin-1 targeted mechanism, in this study, we further uncovered a caveolin-1 dependent mechanism within the activation of PPARγ by the specific agonist GW1929. First, effective knockdown of caveolin-1 by small-interfering RNA (siRNA) markedly abolished the upregulation of GW1929 on PPARγ expression at both mRNA and protein levels; Then, in HEK293T, which has previously been reported with low endogenous caveolin-1 expression, exogenous expression of caveolin-1 significantly enhanced the upregulation of GW1929 on PPARγ expression compared with nontransfection control. In addition, inhibition of PPARγ by either siRNA or pharmacological inhibitor T0070907 led to increased phosphorylation of cellular mitogen-activated protein kinases ERK1/2 and p38. In parallel, GW1929 dramatically decreased the expression of the proliferative regulators (cyclin D1 and PCNA), whereas it increased the apoptotic factors (p21, p53, and mdm2) in hypoxic PASMCs. Furthermore, these effects of GW1929 could be partially reversed by recovery of the drug treatment. In combination, PPARγ activation by GW1929 reversibly drove the cell toward an antiproliferative and proapoptotic phenotype in a caveolin-1-dependent and -targeted mechanism.
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Affiliation(s)
- Kai Yang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Mingming Zhao
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health , Baltimore, Maryland
| | - Junyi Huang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Chenting Zhang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Qiuyu Zheng
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Yuqin Chen
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Haiyang Jiang
- Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Wenju Lu
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China
| | - Jian Wang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China.,Division of Translational and Regenerative Medicine, Department of Medicine, University of Arizona College of Medicine , Tucson, Arizona
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13
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Huang H, Du W, Brekken RA. Extracellular Matrix Induction of Intracellular Reactive Oxygen Species. Antioxid Redox Signal 2017; 27:774-784. [PMID: 28791881 DOI: 10.1089/ars.2017.7305] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
SIGNIFICANCE The extracellular matrix (ECM) is the noncellular component secreted by cells and is present within all tissues and organs. The ECM provides the structural support required for tissue integrity and also contributes to diseases, including cancer. Many diseases rich in ECM are characterized by changes in reactive oxygen species (ROS) levels that have been shown to have important context-dependent functions. Recent Advances: Many studies have found that the ECM affects ROS production through integrins. The activation of integrins by ECM ligands results in stimulation of multiple pathways that can generate ROS. Furthermore, control of ECM-integrin interaction by matricellular proteins is an underappreciated pathway that functions as an ROS rheostat in remodeling tissues. CRITICAL ISSUES A better understanding of how the ECM affects the generation of intracellular ROS is required for advances in the development of therapeutic strategies that affect or exploit oxidative stress. FUTURE DIRECTIONS Targeting ROS generation can be therapeutic or can promote disease progression in a context-dependent manner. Many ECM proteins can impact ROS generation. However, given the breadth of different proteins that constitute the ECM and the cell surface receptors that interact with ECM proteins, there are likely many tissue and microenvironmental-specific ROS-generating pathways that have yet to be investigated in depth. Identifying canonical pathways of ECM-induced ROS generation should be a priority for the field. Antioxid. Redox Signal. 27, 774-784.
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Affiliation(s)
- Huocong Huang
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas
| | - Wenting Du
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas
| | - Rolf A Brekken
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas.,2 Department of Pharmacology, UT Southwestern, Dallas, Texas
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14
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Zhu B, Rippe C, Thi Hien T, Zeng J, Albinsson S, Stenkula KG, Uvelius B, Swärd K. Similar regulatory mechanisms of caveolins and cavins by myocardin family coactivators in arterial and bladder smooth muscle. PLoS One 2017; 12:e0176759. [PMID: 28542204 PMCID: PMC5444588 DOI: 10.1371/journal.pone.0176759] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 04/17/2017] [Indexed: 12/22/2022] Open
Abstract
Caveolae are membrane invaginations present at high densities in muscle and fat. Recent work has demonstrated that myocardin family coactivators (MYOCD, MKL1), which are important for contractile differentiation and cell motility, increase caveolin (CAV1, CAV2, CAV3) and cavin (CAVIN1, CAVIN2, CAVIN3) transcription, but several aspects of this control mechanism remain to be investigated. Here, using promoter reporter assays we found that both MKL1/MRTF-A and MKL2/MRTF-B control caveolins and cavins via their proximal promoter sequences. Silencing of MKL1 and MKL2 in smooth muscle cells moreover reduced CAV1 and CAVIN1 mRNA levels by well over 50%, as did treatment with second generation inhibitors of MKL activity. GATA6, which modulates expression of smooth muscle-specific genes, reduced CAV1 and CAV2, whereas the cavins were unaffected or increased. Viral overexpression of MKL1 and myocardin induced caveolin and cavin expression in bladder smooth muscle cells from rats and humans and MYOCD correlated tightly with CAV1 and CAVIN1 in human bladder specimens. A recently described activator of MKL-driven transcription (ISX) failed to induce CAV1/CAVIN1 which may be due to an unusual transactivation mechanism. In all, these findings further support the view that myocardin family coactivators are important transcriptional drivers of caveolins and cavins in smooth muscle.
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Affiliation(s)
- Baoyi Zhu
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- Department of Urology, the Sixth Affiliated Hospital of Guangzhou Medical University, Guangdong, China
| | - Catarina Rippe
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tran Thi Hien
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Jianwen Zeng
- Department of Urology, the Sixth Affiliated Hospital of Guangzhou Medical University, Guangdong, China
| | | | - Karin G. Stenkula
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Bengt Uvelius
- Department of Urology, Clinical Sciences, Lund University, Lund, Sweden
| | - Karl Swärd
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- * E-mail:
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15
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Rosiglitazone drives cavin-2/SDPR expression in adipocytes in a CEBPα-dependent manner. PLoS One 2017; 12:e0173412. [PMID: 28278164 PMCID: PMC5344386 DOI: 10.1371/journal.pone.0173412] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/10/2017] [Indexed: 12/26/2022] Open
Abstract
Caveolae are abundant adipocyte surface domains involved in insulin signaling, membrane trafficking and lipid homeostasis. Transcriptional control mechanisms for caveolins and cavins, the building blocks of caveolae, are thus arguably important for adipocyte biology and studies in this area may give insight into insulin resistance and diabetes. Here we addressed the hypothesis that one of the less characterized caveolar components, cavin-2 (SDPR), is controlled by CCAAT/Enhancer Binding Protein (CEBPα) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG). Using human mRNA expression data we found that SDPR correlated with PPARG in several tissues. This was also observed during differentiation of 3T3-L1 fibroblasts into adipocytes. Treatment of 3T3-L1-derived adipocytes with the PPARγ-activator Rosiglitazone increased SDPR and CEBPα expression at both the mRNA and protein levels. Silencing of CEBPα antagonized these effects. Further, adenoviral expression of PPARγ/CEBPα or Rosiglitazone-treatment increased SDPR expression in primary rat adipocytes. The myocardin family coactivator MKL1 was recently shown to regulate SDPR expression in human coronary artery smooth muscle cells. However, we found that actin depolymerization, known to inhibit MKL1 and MKL2, was without effect on SDPR mRNA levels in adipocytes, even though overexpression of MKL1 and MKL2 had the capacity to increase caveolins and cavins and to repress PPARγ/CEBPα. Altogether, this work demonstrates that CEBPα expression and PPARγ-activity promote SDPR transcription and further supports the emerging notion that PPARγ/CEBPα and MKL1/MKL2 are antagonistic in adipocytes.
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16
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Shimizu K, Kirita K, Aokage K, Kojima M, Hishida T, Kuwata T, Fujii S, Ochiai A, Funai K, Yoshida J, Tsuboi M, Ishii G. Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma. J Cancer Res Clin Oncol 2017; 143:321-328. [PMID: 27771795 DOI: 10.1007/s00432-016-2285-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 10/07/2016] [Indexed: 10/20/2022]
Abstract
PURPOSE Caveolin is an essential constituent of caveolae and has many biological functions. Expression of caveolin-1 in cancer cells was reported to be a prognostic marker in several types of cancers, the prognostic significance of its expression in cancer-associated fibroblasts (CAFs) has not been investigated. This study aimed to evaluate the clinicopathological significance of expression by CAFs in lung adenocarcinoma. METHODS We examined caveolin-1 expression in both CAFs and cancer cells in stage I invasive lung adenocarcinoma (n = 412) and analyzed the relationship between the expression and clinicopathological factors. RESULTS Caveolin-1 expression by CAFs and cancer cells was observed in 12.1% and 7.8% of adenocarcinomas, respectively. Tumors with caveolin-1-positive CAFs had vascular and pleural invasion significantly more frequently than those with caveolin-1-negative CAF (p < 0.05). This was also the cases with tumors with caveolin-1-positive cancer cells (p < 0.01). Caveolin-1 expression by CAFs and that by cancer cells were significant predictors of shorter recurrence-free survival (p < 0.001). Caveolin-1 expression by CAFs and cancer cells was found in 25% and 30% of solid predominant subtype, respectively, but only 9.2% and 2.7% of non-solid predominant subtype, respectively. The frequency of cases with caveolin-1-positive CAFs or cancer cells was significantly higher in the solid predominant subtype than in non-solid predominant subtype (p < 0.001). CONCLUSIONS Our current results highlight the prognostic importance of caveolin-1 expression by CAFs in stage I lung adenocarcinoma and provide new insights into the biological significance of caveolin-1 in the tumor microenvironment, especially in microenvironment of solid predominant adenocarcinoma.
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Affiliation(s)
- Kei Shimizu
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Keisuke Kirita
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Keiju Aokage
- Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Motohiro Kojima
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Tomoyuki Hishida
- Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takeshi Kuwata
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Satoshi Fujii
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Atsushi Ochiai
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kazuhito Funai
- First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Junji Yoshida
- Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Masahiro Tsuboi
- Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Genichiro Ishii
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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17
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Koizume S, Miyagi Y. Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia. Int J Mol Sci 2016; 17:ijms17091430. [PMID: 27589734 PMCID: PMC5037709 DOI: 10.3390/ijms17091430] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/15/2016] [Accepted: 08/24/2016] [Indexed: 12/20/2022] Open
Abstract
The Warburg effect describes the phenomenon by which cancer cells obtain energy from glycolysis even under normoxic (O₂-sufficient) conditions. Tumor tissues are generally exposed to hypoxia owing to inefficient and aberrant vasculature. Cancer cells have multiple molecular mechanisms to adapt to such stress conditions by reprogramming the cellular metabolism. Hypoxia-inducible factors are major transcription factors induced in cancer cells in response to hypoxia that contribute to the metabolic changes. In addition, cancer cells within hypoxic tumor areas have reduced access to serum components such as nutrients and lipids. However, the effect of such serum factor deprivation on cancer cell biology in the context of tumor hypoxia is not fully understood. Cancer cells are lipid-rich under normoxia and hypoxia, leading to the increased generation of a cellular organelle, the lipid droplet (LD). In recent years, the LD-mediated stress response mechanisms of cancer cells have been revealed. This review focuses on the production and functions of LDs in various types of cancer cells in relation to the associated cellular environment factors including tissue oxygenation status and metabolic mechanisms. This information will contribute to the current understanding of how cancer cells adapt to diverse tumor environments to promote their survival.
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Affiliation(s)
- Shiro Koizume
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan.
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan.
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18
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Ke T, Dorajoo R, Han Y, Khor CC, van Dam RM, Yuan JM, Koh WP, Liu J, Teo YY, Goh DYT, Tai ES, Wong TY, Cheng CY, Friedlander Y, Heng CK. Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population. Ann Hum Genet 2016; 80:282-93. [PMID: 27530449 DOI: 10.1111/ahg.12164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 11/30/2022]
Abstract
Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) < 0.2) were selected. The effect of interactions between PPAR SNPs and those across the genome on HDL-C was tested using linear regression models. One statistically significant interaction influencing HDL-C was detected between PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, β = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population.
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Affiliation(s)
- Tingjing Ke
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Yi Han
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.,Duke-NUS Graduate Medical School, Singapore
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Yik Ying Teo
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.,Department of Statistics and Applied Probability, National University of Singapore, Singapore
| | - Daniel Y T Goh
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - E Shyong Tai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Tien Yin Wong
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore.,Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ching-Yu Cheng
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore.,Academic Medicine Research Institute, Duke-NUS Graduate Medical School, National University of Singapore, Singapore
| | - Yechiel Friedlander
- School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
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19
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Zhao YL, Song JN, Ma XD, Zhang BF, Li DD, Pang HG. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression. Neural Regen Res 2016; 11:944-50. [PMID: 27482223 PMCID: PMC4962592 DOI: 10.4103/1673-5374.184493] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser404(p-tau (S404)), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S404) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.
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Affiliation(s)
- Yong-Lin Zhao
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jin-Ning Song
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xu-Dong Ma
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Bin-Fei Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Dan-Dong Li
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Hong-Gang Pang
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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20
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Yang K, Lu W, Jiang Q, Yun X, Zhao M, Jiang H, Wang J. Peroxisome Proliferator-Activated Receptor γ-Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1-Dependent Mechanism. Am J Respir Cell Mol Biol 2016; 53:882-92. [PMID: 26020612 DOI: 10.1165/rcmb.2015-0002oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Our previous publication demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) inhibits the pathogenesis of chronic hypoxia (CH)-induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process of PPARγ on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O2) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1-fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn(2+) quenching and extracellular Ca(2+) restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up-regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARγ agonist, GW1929, we detected that PPARγ activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARγ on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARγ and caveolin-1, and PPARγ antagonist, T0070907, we observed that PPARγ plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARγ inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs.
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Affiliation(s)
- Kai Yang
- 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Wenju Lu
- 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Qian Jiang
- 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Xin Yun
- 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Mingming Zhao
- 3 Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland
| | - Haiyang Jiang
- 2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Jian Wang
- 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,4 Division of Pulmonary, the People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China.,2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
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21
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Christian M. Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue. Horm Mol Biol Clin Investig 2016; 14:87-97. [PMID: 25436723 DOI: 10.1515/hmbci-2013-0028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 06/10/2013] [Indexed: 01/18/2023]
Abstract
In adipose tissues, nuclear receptors (NRs) have important metabolic actions on cellular lipid-storing capacity through targeted gene regulation. Lipid droplets (LDs) are the organelles for intracellular triacylglycerol (TAG) storage and are present in all eukaryotic cells. They are small in most cells, but in white adipocytes, they can occupy 90% of the cytoplasm. LDs consist of a TAG core surrounded by a phospholipid monolayer and an array of associated proteins that determine size, stability, inter-droplet interaction, and lipid storage capacity. The genes that encode these proteins are more highly expressed in brown compared with white fat, correlating with the greater LD surface area in multilocular brown adipocytes. Gene expression profiling reveals that most NRs are present in adipose tissues, with some showing greater expression in brown compared with white fat, including peroxisome proliferator-activated receptor (PPAR) α, estrogen-related receptor α, and NURR1. NR signaling is important for the regulated expression of most genes that encode LD-associated proteins. For example, estradiol signals via estrogen receptor α to regulate the levels of PLIN1 and the lipase ATGL controlling LD size and total lipid accumulation. PPARγ is essential for adipocyte differentiation and function, and analysis of data obtained through chromatin immunoprecipitation followed by high-throughput DNA sequencing shows that it binds to the promoters of many genes encoding LD proteins in adipocytes. Of these genes, the greatest PPARγ binding was to regulatory regions for Plin1, Cidec, and G0s2. NRs represent an important target for controlling LD dynamics in diseases affected by altered fat storage encompassing obesity and lipodystrophy, which are an increasing health problem.
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Affiliation(s)
- Mark Christian
- Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
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Huang J, Wolk JH, Gewitz MH, Loyd JE, West J, Austin ED, Mathew R. Enhanced caveolin-1 expression in smooth muscle cells: Possible prelude to neointima formation. World J Cardiol 2015; 7:671-684. [PMID: 26516422 PMCID: PMC4620079 DOI: 10.4330/wjc.v7.i10.671] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/24/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the genesis of neointima formation in pulmonary hypertension (PH), we investigated the role of caveolin-1 and related proteins.
METHODS: Male Sprague Dawley rats were given monocrotaline (M, 40 mg/kg) or subjected to hypobaric hypoxia (H) to induce PH. Another group was given M and subjected to H to accelerate the disease process (M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor (PPAR) γ, caveolin-2, proliferative and anti-apoptotic factors (PY-STAT3, p-Erk, Bcl-xL), endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue.
RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells (SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in eNOS and HSP90 expression was present in the M groups (2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups.
CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.
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Kole L, Sarkar M, Deb A, Giri B. Pioglitazone, an anti-diabetic drug requires sustained MAPK activation for its anti-tumor activity in MCF7 breast cancer cells, independent of PPAR-γ pathway. Pharmacol Rep 2015; 68:144-54. [PMID: 26721366 DOI: 10.1016/j.pharep.2015.08.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 07/29/2015] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND The thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor gamma (PPAR-γ) ligands are known for their ability to induce adipocyte differentiation, to increase insulin sensitivity including anticancer properties. But, whether or not upstream events like MAPK activation or PPAR-γ signaling are involved or associated with this anticancer activity is not well understood in breast cancer cells. The role of MAPK and PPAR pathways during the pioglitazone (Pio) induced PPAR-γ independent anticancer activity in MCF7 cells has been focused here. METHODS The anticancer activity of Pio has been investigated in breast cancer cells in vitro. Anti-tumor effects were assessed by alamar blue assay, Western blot analysis, cell cycle analysis, and annexin V-FITC/PI binding assay by flow cytometry, Hoechst staining and luciferase assay. RESULTS The anticancer activity of Pio is found to be correlating with the up regulation of CDKIs (p21/p27) and down regulation of CDK-4. This study demonstrates that the induction of CDKIs by Pio is due to the sustained activation of MAPK. The Pio-mediated activation of MAPK is transmitted to activate ELK-1 and the related anti-proliferation is blocked by MEK inhibitor (PD-184352). CONCLUSIONS Pio suppresses the proliferation of MCF7 cells, at least partly by a PPAR-γ-independent mechanism involving the induction of p21 which in turn requires sustained activation of MAPK. These findings implicate the utility of Pio in the treatment of PPAR positive or negative human cancers and the development of a new class of compounds to enhance the effectiveness of Pio.
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Affiliation(s)
- Labanyamoy Kole
- Discovery Research SBU, Dr. Reddy's Laboratories Ltd., Hyderabad, India
| | - Mrinmoy Sarkar
- Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India
| | - Anwesha Deb
- Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India
| | - Biplab Giri
- Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India.
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Abstract
Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.
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25
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Martin RIR, Babaei MS, Choy MK, Owens WA, Chico TJA, Keenan D, Yonan N, Koref MS, Keavney BD. Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC. J Mol Cell Cardiol 2015; 85:207-14. [PMID: 26073630 DOI: 10.1016/j.yjmcc.2015.06.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 04/30/2015] [Accepted: 06/01/2015] [Indexed: 12/17/2022]
Abstract
Genome-wide association studies (GWAS) have identified genetic variants in a number of chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown, but are likely to involve effects of the risk haplotypes on expression of neighbouring genes. To investigate the association between genetic variants at AF-associated loci and expression of nearby candidate genes in human atrial tissue and peripheral blood. Right atrial appendage (RAA) samples were collected from 122 patients undergoing cardiac surgery, of these, 12 patients also had left atrial appendage samples taken. 22 patients had a history of AF. Peripheral blood samples were collected from 405 patients undergoing diagnostic cardiac catheterisation. In order to tag genetic variation at each of nine loci, a total of 367 single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom platform. Total expression of 16 candidate genes in the nine AF-associated regions was measured by quantitative PCR. The relative expression of each allele of the candidate genes was measured on the Sequenom platform using one or more transcribed SNPs to distinguish between alleles in heterozygotes. We tested association between the SNPs of interest and gene expression using total gene expression (integrating cis and trans acting sources of variation), and allelic expression ratios (specific for cis acting influences), in atrial tissue and peripheral blood. We adjusted for multiple comparisons using a Bonferroni approach. In subsidiary analyses, we compared the expression of candidate genes between patients with and without a history of AF. Total expression of 15 transcripts of 14 genes and allelic expression ratio of 14 transcripts of 14 genes in genomic regions associated with AF were measured in right atrial appendage tissue. 8 of these transcripts were also expressed in peripheral blood. Risk alleles at AF-associated SNPs were associated in cis with an increased expression of PITX2a (2.01-fold, p=6.5×10(-4)); and with decreased expression of MYOZ1 (0.39 fold; p=5.5×10(-15)), CAV1 (0.89 fold; p=5.9×10(-8)), C9orf3 (0.91 fold; 1.5×10(-5)), and FANCC (0.94-fold; p=8.9×10(-8)) in right atrial appendage. Of these five genes, only CAV1 was expressed in peripheral blood; association between the same AF risk alleles and lower expression of CAV1 was confirmed (0.91 fold decrease; p=4.2×10(-5)). A history of AF was also associated with a decrease in expression of CAV1 in both right and left atria (0.84 and 0.85 fold, respectively; p=0.03), congruent with the magnitude of the effect of the risk SNP on expression, and independent of genotype. The analyses in peripheral blood showed association between AF risk SNPs and decreased expression of KCNN3 (0.85-fold; p=2.1×10(-4)); and increased expression of SYNE2 (1.12-fold; p=7.5×10(-24)); however, these associations were not detectable in atrial tissue. We identified novel cis-acting associations in atrial tissue between AF risk SNPs and increased expression of PITX2a/b; and decreased expression of CAV1 (an association also seen in peripheral blood), C9orf3 and FANCC. We also confirmed a previously described association between AF risk variants and MYOZ1 expression. Analyses of peripheral blood illustrated tissue-specificity of cardiac eQTLs and highlight the need for larger-scale genome-wide eQTL studies in cardiac tissue. Our results suggest novel aetiological roles for genes in four AF-associated genomic regions.
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Affiliation(s)
- Ruairidh I R Martin
- Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
| | | | - Mun-Kit Choy
- Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | - W Andrew Owens
- Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK; Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
| | | | - Daniel Keenan
- Manchester Heart Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Nizar Yonan
- North West Heart Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
| | | | - Bernard D Keavney
- Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK; Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
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Mahmoud AM, Abdella EM, El-Derby AM, Abdella EM. Protective Effects of Turbinaria ornata and Padina pavonia against Azoxymethane-Induced Colon Carcinogenesis through Modulation of PPAR Gamma, NF-κB and Oxidative Stress. Phytother Res 2015; 29:737-48. [PMID: 25676613 DOI: 10.1002/ptr.5310] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 01/22/2015] [Accepted: 01/22/2015] [Indexed: 12/16/2023]
Abstract
The aim of this study was to investigate the antiproliferative and protective effects of the brown seaweeds, Turbinaria ornata and Padina pavonia, against azoxymethane (AOM)-induced colon carcinogenesis in mice. Both algal extracts showed anti-proliferative effects on the human carcinoma cell line HCT-116 in vitro, with T. ornata demonstrating a more potent effect. Male albino Swiss mice received intraperitoneal injections of AOM (10 mg/kg) once a week for two consecutive weeks and 100 mg/kg of either T. ornata or P. pavonia extracts. AOM-induced mice exhibited alterations in the histological structure of the colon, elevated lipid peroxidation and nitric oxide, declined glutathione content and reduced activity of superoxide dismutase and glutathione peroxidase. In addition, AOM induced downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and p53 mRNA expression, with concomitant upregulation of nuclear factor-kappa B (NF-κB) in colon tissue. Administration of either algal extract markedly alleviated the recorded alterations. In conclusion, the current study suggests that T. ornata and P. pavonia, through their antioxidant and anti-inflammatory effects, are able to attenuate colon inflammation by downregulating NF-κB expression. Furthermore, the protective effects of both algae against AOM-initiated carcinogenesis were attributed, at least in part, to their ability to upregulate colonic PPARγ and p53 expression.
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Affiliation(s)
- Ayman M Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Egypt
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27
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Vered M, Lehtonen M, Hotakainen L, Pirilä E, Teppo S, Nyberg P, Sormunen R, Zlotogorski-Hurvitz A, Salo T, Dayan D. Caveolin-1 accumulation in the tongue cancer tumor microenvironment is significantly associated with poor prognosis: an in-vivo and in-vitro study. BMC Cancer 2015; 15:25. [PMID: 25633184 PMCID: PMC4318139 DOI: 10.1186/s12885-015-1030-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 01/20/2015] [Indexed: 12/27/2022] Open
Abstract
Background Caveolin-1 (CAV1) may be upregulated by hypoxia and acts in a tumor-dependent manner. We investigated CAV1 in tongue squamous cell carcinoma (TSCC) and its association with clinical outcomes, and studied in vitro possible ways for CAV1 accumulation in the tumor microenvironment (TME). Methods TSCC cases (N = 64) were immunohistochemically stained for CAV1. Scores were separately assessed in the tumor and TME and plotted for association with recurrence and survival (univariate analysis with log-rank test). In vitro studies were performed on a 3D myoma organotypic model, a mimicker of TME. Prior to monoculturing HSC-3 tongue cancer cells, the model underwent modifications in oxygenation level (1%O2 hypoxia to upregulate CAV1) and/or in the amount of natural soluble factors [deleted by 14-day rinsing (rinsed myoma, RM), to allow only HSC-3-derived factors to act]. Controls included normoxia (21%O2) and naturally occurring soluble factors (intact myoma, IM). HSC-3 cells were also co-cultured with CaDEC12 cells (fibroblasts exposed to human tongue cancer). CAV1 expression and cellular distribution were examined in different cellular components in hypoxic and rinsed myoma assays. Twist served as a marker for the process of epithelial-mesenchymal transition (EMT). Exosomes isolated from HSC-3 media were investigated for containing CAV1. Results Expression of CAV1 in TSCC had a higher score in TME than in the tumor cells and a negative impact on recurrence (p = 0.01) and survival (p = 0.003). Monocultures of HSC-3 revealed expression of CAV1 mainly in the TME-like myoma assay, similar to TSCC. CAV1+, alpha-smooth muscle actin (αSMA) + and Twist + CAF-like cells were observed surrounding the invading HSC-3, possibly reflecting EMT. RM findings were similar to IM, inferring action of HSC-3 derived factors, and no differences were seen when hypoxia was induced. HSC-3-CaDEC12 co-cultures revealed CAV1+, αSMA+ and cytokeratin-negative CAF-like cells, raising the possibility of CaDEC12 cells gaining a CAF phenotype. HSC-3-derived exosomes were loaded with CAV1. Conclusions Accumulation of CAV1-TME in TSCC had a negative prognostic value. In vitro studies showed the presence of CAV1 in cancer cells undergoing EMT and in fibroblasts undergoing trans-differentiation to CAFs. CAV1 delivery to the TME involved cancer cell-derived exosomes.
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Affiliation(s)
- Marilena Vered
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. .,Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
| | - Meri Lehtonen
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland.
| | - Lari Hotakainen
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland.
| | - Emma Pirilä
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland.
| | - Susanna Teppo
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland.
| | - Pia Nyberg
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland. .,Oulu University Hospital, Oulu, Finland.
| | - Raija Sormunen
- Biocenter Oulu, University of Oulu, Oulu, Finland. .,Medical Research Center, Oulu, Finland.
| | - Ayelet Zlotogorski-Hurvitz
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
| | - Tuula Salo
- Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland. .,Oulu University Hospital, Oulu, Finland. .,Biocenter Oulu, University of Oulu, Oulu, Finland. .,Medical Research Center, Oulu, Finland. .,Institute of Dentistry, University of Helsinki, Helsinki, Finland.
| | - Dan Dayan
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
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Gupta R, Toufaily C, Annabi B. Caveolin and cavin family members: dual roles in cancer. Biochimie 2014; 107 Pt B:188-202. [PMID: 25241255 DOI: 10.1016/j.biochi.2014.09.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 09/04/2014] [Indexed: 12/16/2022]
Abstract
Caveolae are specialized plasma membrane subdomains with distinct lipid and protein compositions, which play an essential role in cell physiology through regulation of trafficking and signaling functions. The structure and functions of caveolae have been shown to require the proteins caveolins. Recently, members of the cavin protein family were found to be required, in concert with caveolins, for the formation and function of caveolae. Caveolins have a paradoxical role in the development of cancer formation. They have been involved in both tumor suppression and oncogenesis, depending on tumor type and progress stage. High expression of caveolins and cavins leads to inhibition of cancer-related pathways, such as growth factor signaling pathways. However, certain cancer cells that express caveolins and cavins have been shown to be more aggressive and metastatic because of their increased potential for anchorage-independent growth. Here, we will survey the functional roles of caveolins and of different cavin family members in cancer regulation.
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Affiliation(s)
- Reshu Gupta
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada.
| | - Chirine Toufaily
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
| | - Borhane Annabi
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
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Cheng MF, Song JN, Li DD, Zhao YL, An JY, Sun P, Luo XH. The role of rosiglitazone in the proliferation of vascular smooth muscle cells after experimental subarachnoid hemorrhage. Acta Neurochir (Wien) 2014; 156:2103-9. [PMID: 25139403 DOI: 10.1007/s00701-014-2196-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 07/23/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Recent evidence has demonstrated that rosiglitazone can attenuate cerebral vasospasm following subarachnoid hemorrhage (SAH). Some studies have shown that rosiglitazone can suppress inflammation and immune responses after SAH. However, the precise molecular mechanisms by which cerebral vasospasm is attenuated is not clear. METHODS In this study, SAH was created using a "double hemorrhage" injection rat model. Rats were randomly divided into three groups and treated with saline (control group), untreated (SAH group), or treated with rosiglitazone. Using immunocytochemistry, hematoxylin and eosin (HE) staining, and measurement of the basilar artery, we investigated the formation of pathologic changes in the basilar artery, measured the expression of caveolin-1 and proliferating cell nuclear antigen (PCNA), and investigated the role of rosiglitazone in vascular smooth muscle cell (VSMC) proliferation in the basilar artery after SAH. RESULTS In this study, we observed significant pathologic changes in the basilar artery after experimental SAH. The level of vasospasm gradually increased with time during the 1st week, peaked on day 7, and almost recovered on day 14. After rosiglitazone treatment, the level of vasospasm was significantly attenuated in comparison with the SAH group. Immunocytochemistry staining showed that caveolin-1 expression was significantly increased in the rosiglitazone group, compared with the SAH group. Inversely, the expression of PCNA showed a notable decrease after rosiglitazone treatment. CONCLUSIONS The results indicate that rosiglitazone can attenuate cerebral vasospasm following SAH. Up-regulation of caveolin-1 by rosiglitazone may be a new molecular mechanism for this response, which is to inhibit proliferation of VSMCs after SAH, and this study may provide a novel insight to prevent delayed cerebral vasospasm (DCVS).
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MESH Headings
- Animals
- Basilar Artery/drug effects
- Basilar Artery/pathology
- Caveolin 1/drug effects
- Caveolin 1/metabolism
- Cell Proliferation/drug effects
- Disease Models, Animal
- Immunohistochemistry
- Male
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Proliferating Cell Nuclear Antigen/drug effects
- Proliferating Cell Nuclear Antigen/metabolism
- Rats
- Rats, Sprague-Dawley
- Rosiglitazone
- Subarachnoid Hemorrhage/complications
- Subarachnoid Hemorrhage/pathology
- Subarachnoid Hemorrhage/physiopathology
- Thiazolidinediones/pharmacology
- Up-Regulation
- Vasoconstriction/drug effects
- Vasodilator Agents/pharmacology
- Vasospasm, Intracranial/etiology
- Vasospasm, Intracranial/physiopathology
- Vasospasm, Intracranial/prevention & control
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Affiliation(s)
- Mao-Feng Cheng
- Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
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Mathew R. Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1. World J Cardiol 2014; 6:692-705. [PMID: 25228949 PMCID: PMC4163699 DOI: 10.4330/wjc.v6.i8.692] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/29/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
A number of disparate diseases can lead to pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro- and anti-inflammatory adipokines that modulate vascular function and angiogenesis, suggesting a close functional relationship between the adipose tissue and the vasculature. Both caveolin-1, a cell membrane scaffolding protein and peroxisome proliferator-activated receptor (PPAR) γ, a ligand-activated transcription factor are abundantly expressed in the endothelial cells and adipocytes. Both caveolin-1 and PPARγ modulate proliferative and anti-apoptotic pathways, cell migration, inflammation, vascular homeostasis, and participate in lipid transport, triacylglyceride synthesis and glucose metabolism. Caveolin-1 and PPARγ regulate the production of adipokines and in turn are modulated by them. This review article summarizes the roles and inter-relationships of caveolin-1, PPARγ and adipokines in PH and metabolic syndrome.
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Zhang Y, Yang X, Bian F, Wu P, Xing S, Xu G, Li W, Chi J, Ouyang C, Zheng T, Wu D, Zhang Y, Li Y, Jin S. TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: Crosstalk between NF-κB and PPAR-γ. J Mol Cell Cardiol 2014; 72:85-94. [DOI: 10.1016/j.yjmcc.2014.02.012] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 02/21/2014] [Accepted: 02/24/2014] [Indexed: 01/17/2023]
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Anderson JL, Keeley MC, Smith SC, Smith EC, Taylor RL. Rosiglitazone modulates pigeon atherosclerotic lipid accumulation and gene expression in vitro. Poult Sci 2014; 93:1368-74. [PMID: 24879686 PMCID: PMC4988620 DOI: 10.3382/ps.2013-03840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/25/2014] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis is a major contributor to the overall United States mortality rate, primarily in the form of heart attacks and stroke. Unlike the human disease, which is believed to be multifactorial, pigeon atherosclerosis is due to a single gene autosomal recessive trait. The White Carneau (WC-As) strain develops atherosclerotic plaques without the presence of known environmental risk factors such as diet and classic predictors such as blood pressure or blood cholesterol levels. With similar parameters, the Show Racer (SR-Ar) is resistant to plaque development. Thiazolidinediones, including rosiglitazone, activate the peroxisome proliferator-activated receptor gamma (PPARγ) raising cellular sensitivity to insulin. The effect of rosiglitazone was evaluated in aortic smooth muscle cells (SMC) from these 2 pigeon breeds. Primary SMC cultures were prepared from WC-As and SR-Ar squabs. Cell monolayers, which achieved confluence in 7 d, were treated with 0 or 4 µM rosiglitazone for 24 h. Cellular lipid accumulation was evaluated by oil red O staining. Control WC-As cells had significantly higher vacuole scores and lipid content than did the SR-Ar control cells. Rosiglitazone treatment decreased WC-As lipid vacuoles significantly compared with the control cells. On the other hand, lipid vacuoles in the treated and untreated SR-Ar cells did not differ significantly. The effect of rosiglitazone on WC-As SMC gene expression was compared with control SMC using representational difference analysis. Significant transcript increases were found for caveolin and RNA binding motif in the control cells compared with the rosiglitazone-treated cells as well as cytochrome p450 family 17 subfamily A polypeptide 1 (CYP171A) in the rosiglitazone-treated cells compared with the control cells. Although rosiglitazone was selected for these experiments because of its role as a PPARγ agonist, it appears that the drug also tempers c-myc expression, as genes related to this second transcription factor were differentially expressed. Both PPARγ and c-myc appear to affect WC-As SMC gene expression, which may relate to disease development, progression, or both.
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Affiliation(s)
- J L Anderson
- Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824
| | - M C Keeley
- Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824
| | - S C Smith
- Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824
| | - E C Smith
- Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824
| | - R L Taylor
- Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824
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Shashni B, Sharma K, Singh R, Sakharkar KR, Dhillon SK, Nagasaki Y, Sakharkar MK. Coffee component hydroxyl hydroquinone (HHQ) as a putative ligand for PPAR gamma and implications in breast cancer. BMC Genomics 2013; 14 Suppl 5:S6. [PMID: 24564733 PMCID: PMC3852186 DOI: 10.1186/1471-2164-14-s5-s6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Coffee contains several compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee compounds and breast cancer survival are sparse and inconsistent. Results We show that coffee component HHQ has significant apoptotic effect on MDA-MB-231 and MCF-7 cells in vitro, and that ROS generation, change in mitochondrial membrane permeability, upregulation of Bax and Caspase-8 as well as down regulation of PGK1 and PKM2 expression may be important apoptosis-inducing mechanisms. The results suggest that PPARγ ligands may serve as potential therapeutic agents for breast cancer therapy. HHQ was also validated as a ligand for PPARγ by docking procedure. Conclusion This is the first report on the anti-breast cancer (in vitro) activity of HHQ.
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Siddiqui RA, Harvey KA, Walker C, Altenburg J, Xu Z, Terry C, Camarillo I, Jones-Hall Y, Mariash C. Characterization of synergistic anti-cancer effects of docosahexaenoic acid and curcumin on DMBA-induced mammary tumorigenesis in mice. BMC Cancer 2013; 13:418. [PMID: 24034496 PMCID: PMC3848456 DOI: 10.1186/1471-2407-13-418] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 09/09/2013] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice. METHODS We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey's post hoc procedure. RESULTS Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of "PAM50" genes in the SK-BR-3 cell line from an ER⁻/Her-2⁺ to that resembling a "normal-like" phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin. CONCLUSIONS The SK-BR-3 cells and DMBA-induced tumors, both with an ER⁻ and Her-2⁺ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.
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Affiliation(s)
- Rafat A Siddiqui
- Cellular Biochemistry Laboratory, Indiana University Health, Indianapolis, IN 46202, USA.
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Friedrich T, Richter B, Gaiser T, Weiss C, Janssen KP, Einwächter H, Schmid RM, Ebert MPA, Burgermeister E. Deficiency of caveolin-1 in Apc(min/+) mice promotes colorectal tumorigenesis. Carcinogenesis 2013; 34:2109-18. [PMID: 23640045 DOI: 10.1093/carcin/bgt142] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.
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Affiliation(s)
- Teresa Friedrich
- Department of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany
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Her NG, Jeong SI, Cho K, Ha TK, Han J, Ko KP, Park SK, Lee JH, Lee MG, Ryu BK, Chi SG. PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway. Cell Cycle 2013; 12:1521-35. [PMID: 23598720 DOI: 10.4161/cc.24636] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
TGF-β1 plays biphasic functions in prostate tumorigenesis, inhibiting cell growth at early stages but promoting malignant progression at later stages. However, the molecular basis for the oncogenic conversion of TGF-β1 function remains largely undefined. Here, we demonstrate that PPARδ is a direct transcription target of TGF-β1 and plays a critical role in oncogenic redirection of TGF-β1 signaling. Blockade of PPARδ induction enhances tumor cell response to TGF-β1-mediated growth inhibition, while its activation promotes TGF-β1-induced tumor growth, migration and invasion. PPARδ-mediated switch of TGF-β1 function is associated with down- and upregulation of Smad and ERK signaling, respectively, and tightly linked to its function to activate ABCA1 cholesterol transporter followed by caveolin-1 (Cav1) induction. Intriguingly, TGF-β1 activation of the PPARδ-ABCA1-Cav1 pathway facilitates degradation of TGF-β receptors (TβRs) and attenuates Smad but enhances ERK response to TGF-β1. Expression of PPARδ and Cav1 is tightly correlated in both prostate tissues and cell lines and significantly higher in cancer vs. normal tissues. Collectively, our study shows that PPARδ is a transcription target of TGF-β1 and contributes to the oncogenic conversion of TGF-β1 function through activation of the ABCA1-Cav1-TβR signaling axis.
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Affiliation(s)
- Nam-Gu Her
- School of Life Sciences and Biotechnology, Korea University, Seoul, Korea
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Mansure JJ, Nassim R, Chevalier S, Szymanski K, Rocha J, Aldousari S, Kassouf W. A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer. PLoS One 2013; 8:e55997. [PMID: 23409107 PMCID: PMC3568080 DOI: 10.1371/journal.pone.0055997] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 01/03/2013] [Indexed: 11/19/2022] Open
Abstract
Background Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy. Principal Findings As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner. Conclusion These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.
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Affiliation(s)
- Jose Joao Mansure
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Roland Nassim
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Simone Chevalier
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Konrad Szymanski
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Joice Rocha
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Saad Aldousari
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
| | - Wassim Kassouf
- McGill Urologic Oncology Research, Division of Urology, McGill University Health Center, Montreal, Quebec, Canada
- * E-mail:
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Vadlamudi HC, Yalavarthi PR, Balambhaigari RY, Vulava J. Receptors and ligands role in colon physiology and pathology. J Recept Signal Transduct Res 2013; 33:1-9. [DOI: 10.3109/10799893.2012.752001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Byrne DP, Dart C, Rigden DJ. Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif? PLoS One 2012; 7:e44879. [PMID: 23028656 PMCID: PMC3444507 DOI: 10.1371/journal.pone.0044879] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 08/09/2012] [Indexed: 01/08/2023] Open
Abstract
Caveolins are coat proteins of caveolae, small flask-shaped pits of the plasma membranes of most cells. Aside from roles in caveolae formation, caveolins recruit, retain and regulate many caveolae-associated signalling molecules. Caveolin-protein interactions are commonly considered to occur between a ∼20 amino acid region within caveolin, the caveolin scaffolding domain (CSD), and an aromatic-rich caveolin binding motif (CBM) on the binding partner (фXфXXXXф, фXXXXфXXф or фXфXXXXфXXф, where ф is an aromatic and X an unspecified amino acid). The CBM resembles a typical linear motif - a short, simple sequence independently evolved many times in different proteins for a specific function. Here we exploit recent improvements in bioinformatics tools and in our understanding of linear motifs to critically examine the role of CBMs in caveolin interactions. We find that sequences conforming to the CBM occur in 30% of human proteins, but find no evidence for their statistical enrichment in the caveolin interactome. Furthermore, sequence- and structure-based considerations suggest that CBMs do not have characteristics commonly associated with true interaction motifs. Analysis of the relative solvent accessible area of putative CBMs shows that the majority of their aromatic residues are buried within the protein and are thus unlikely to interact directly with caveolin, but may instead be important for protein structural stability. Together, these findings suggest that the canonical CBM may not be a common characteristic of caveolin-target interactions and that interfaces between caveolin and targets may be more structurally diverse than presently appreciated.
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Affiliation(s)
- Dominic P. Byrne
- Institute of Integrative Biology, The University of Liverpool, Liverpool, United Kingdom
| | - Caroline Dart
- Institute of Integrative Biology, The University of Liverpool, Liverpool, United Kingdom
| | - Daniel J. Rigden
- Institute of Integrative Biology, The University of Liverpool, Liverpool, United Kingdom
- * E-mail:
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Prade E, Tobiasch M, Hitkova I, Schäffer I, Lian F, Xing X, Tänzer M, Rauser S, Walch A, Feith M, Post S, Röcken C, Schmid RM, Ebert MPA, Burgermeister E. Bile acids down-regulate caveolin-1 in esophageal epithelial cells through sterol responsive element-binding protein. Mol Endocrinol 2012; 26:819-32. [PMID: 22474125 DOI: 10.1210/me.2011-1140] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Bile acids are synthesized from cholesterol and are major risk factors for Barrett adenocarcinoma (BAC) of the esophagus. Caveolin-1 (Cav1), a scaffold protein of membrane caveolae, is transcriptionally regulated by cholesterol via sterol-responsive element-binding protein-1 (SREBP1). Cav1 protects squamous epithelia by controlling cell growth and stabilizing cell junctions and matrix adhesion. Cav1 is frequently down-regulated in human cancers; however, the molecular mechanisms that lead to this event are unknown. We show that the basal layer of the nonneoplastic human esophageal squamous epithelium expressed Cav1 mainly at intercellular junctions. In contrast, Cav1 was lost in 95% of tissue specimens from BAC patients (n = 100). A strong cytoplasmic expression of Cav1 correlated with poor survival in a small subgroup (n = 5) of BAC patients, and stable expression of an oncogenic Cav1 variant (Cav1-P132L) in the human BAC cell line OE19 promoted proliferation. Cav1 was also detectable in immortalized human squamous epithelial, Barrett esophagus (CPC), and squamous cell carcinoma cells (OE21), but was low in BAC cell lines (OE19, OE33). Mechanistically, bile acids down-regulated Cav1 expression by inhibition of the proteolytic cleavage of 125-kDa pre-SREBP1 from the endoplasmic reticulum/Golgi apparatus and nuclear translocation of active 68-kDa SREBP1. This block in SREBP1's posttranslational processing impaired transcriptional activation of SREBP1 response elements in the proximal human Cav1 promoter. Cav1 was also down-regulated in esophagi from C57BL/6 mice on a diet enriched with 1% (wt/wt) chenodeoxycholic acid. Mice deficient for Cav1 or the nuclear bile acid receptor farnesoid X receptor showed hyperplasia and hyperkeratosis of the basal cell layer of esophageal epithelia, respectively. These data indicate that bile acid-mediated down-regulation of Cav1 marks early changes in the squamous epithelium, which may contribute to onset of Barrett esophagus metaplasia and progression to BAC.
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Affiliation(s)
- Elke Prade
- Department of Chemistry, Klinikum rechts der Isar, Technische Universität München, D-81675 Munich, Germany
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Palozza P, Catalano A, Simone R, Mele M, Cittadini A. Effect of Lycopene and Tomato Products on Cholesterol Metabolism. ANNALS OF NUTRITION AND METABOLISM 2012; 61:126-34. [DOI: 10.1159/000342077] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 07/17/2012] [Indexed: 01/01/2023]
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Wang P, Zhu F, Konstantopoulos K. Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-Δ(12,14)-PGJ2. PLoS One 2011; 6:e27630. [PMID: 22096605 PMCID: PMC3214064 DOI: 10.1371/journal.pone.0027630] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 10/20/2011] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E(2), PGD(2) and its dehydration end product 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE(2) directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD(2) and 15d-PGJ(2) in the absence or presence of PGE(2) on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients. METHODOLOGY/PRINCIPAL FINDINGS Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE(2) and PGD(2)/15d-PGJ(2) exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE(2) stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD(2) or 15d-PGJ(2) concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE(2)-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes. CONCLUSIONS/SIGNIFICANCE We have delineated the signaling cascade by which PGE(2) and PGD(2)/15d-PGJ(2) exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.
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Affiliation(s)
- Pu Wang
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Fei Zhu
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Konstantinos Konstantopoulos
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America
- Johns Hopkins Physical Sciences in Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, United States of America
- Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, United States of America
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Lycopene regulation of cholesterol synthesis and efflux in human macrophages. J Nutr Biochem 2011; 22:971-8. [DOI: 10.1016/j.jnutbio.2010.08.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 07/29/2010] [Accepted: 08/05/2010] [Indexed: 11/17/2022]
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PPARgamma: The Portrait of a Target Ally to Cancer Chemopreventive Agents. PPAR Res 2011; 2008:436489. [PMID: 18779870 PMCID: PMC2528242 DOI: 10.1155/2008/436489] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Revised: 05/22/2008] [Accepted: 07/16/2008] [Indexed: 12/13/2022] Open
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPARγ was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPARγ ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPARγ. Overall, PPARγ appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.
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Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. PPARγ plays an important role in adipocyte differentiation, lipid storage and energy dissipation in adipose tissue, and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity. Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors, including colorectal cancer. High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma. This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer, and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.
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Affiliation(s)
- Yun Dai
- Yun Dai, Wei-Hong Wang, Department of Gastroenterology, Peking University First Hospital, Beijing 100034, China
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The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain. Mol Cell Biol 2011; 31:3497-510. [PMID: 21690289 DOI: 10.1128/mcb.01421-10] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARγ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARγ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARγ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARγ and enhanced nuclear translocation and ligand-independent transcription of PPARγ target genes. In contrast, Cav1 overexpression sequestered PPARγ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARγ's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARγ and to inhibit cell proliferation. Ligand-activated PPARγ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARγ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARγ to ligands, limiting proliferation of gastric epithelial cells.
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Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling. Cell Metab 2011; 13:550-61. [PMID: 21531337 DOI: 10.1016/j.cmet.2011.02.015] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 01/10/2011] [Accepted: 02/17/2011] [Indexed: 01/09/2023]
Abstract
Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.
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Crist RC, Roth JJ, Lisanti MP, Siracusa LD, Buchberg AM. Identification of Mom12 and Mom13, two novel modifier loci of Apc (Min) -mediated intestinal tumorigenesis. Cell Cycle 2011; 10:1092-9. [PMID: 21386660 DOI: 10.4161/cc.10.7.15089] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer is a heterogeneous disease resulting from a combination of genetic and environmental factors. The C57BL/6J (B6) Apc (Min/+) mouse develops polyps throughout the gastrointestinal tract and has been a valuable model for understanding the genetic basis of intestinal tumorigenesis. Apc (Min/+) mice have been used to study known oncogenes and tumor suppressor genes on a controlled genetic background. These studies often utilize congenic knockout alleles, which can carry an unknown amount of residual donor DNA. The Apc (Min) model has also been used to identify modifer loci, known as Modifier of Min (Mom) loci, which alter Apc (Min) -mediated intestinal tumorigenesis. B6 mice carrying a knockout allele generated in WW6 embryonic stem cells were crossed to B6 Apc (Min/+) mice to determine the effect on polyp multiplicity. The newly generated colony developed significantly more intestinal polyps than Apc (Min/+) controls. Polyp multiplicity did not correlate with inheritance of the knockout allele, suggesting the presence of one or more modifier loci segregating in the colony. Genotyping of simple sequence length polymorphism (SSLP) markers revealed residual 129X1/SvJ genomic DNA within the congenic region of the parental knockout line. An analysis of polyp multiplicity data and SSLP genotyping indicated the presence of two Mom loci in the colony: 1) Mom12, a dominant modifier linked to the congenic region on chromosome 6, and 2) Mom13, which is unlinked to the congenic region and whose effect is masked by Mom12. The identification of Mom12 and Mom13 demonstrates the potential problems resulting from residual heterozygosity present in congenic lines.
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Affiliation(s)
- Richard C Crist
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA USA
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Peroxisome-proliferator-activated receptor gamma (PPARγ) is required for modulating endothelial inflammatory response through a nongenomic mechanism. Eur J Cell Biol 2010; 89:645-53. [DOI: 10.1016/j.ejcb.2010.04.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Revised: 03/24/2010] [Accepted: 04/07/2010] [Indexed: 02/03/2023] Open
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