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Ranjan G, Ranjan S, Sunita P, Pattanayak SP. Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4705-4725. [PMID: 39621087 DOI: 10.1007/s00210-024-03661-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/20/2024] [Indexed: 04/11/2025]
Abstract
Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.
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Affiliation(s)
- Gaurav Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Shashi Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Priyashree Sunita
- Department of Surgery, Case Comprehensive Cancer Centre, Case Western Reserve University, Wolstein Research Building 2103 Cornell Rd, Cleveland, OH, 44106, USA
| | - Shakti Prasad Pattanayak
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Woods Building, W437, 2109 Adelbert Road, Cleaveland, OH, 44106, USA.
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Sobolev V, Tchepourina E, Soboleva A, Denisova E, Korsunskaya I, Mezentsev A. PPAR-γ in Melanoma and Immune Cells: Insights into Disease Pathogenesis and Therapeutic Implications. Cells 2025; 14:534. [PMID: 40214488 PMCID: PMC11989151 DOI: 10.3390/cells14070534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Changes in skin pigmentation, like hyperpigmentation or moles, can affect appearance and social life. Unlike locally containable moles, malignant melanomas are aggressive and can spread rapidly, disproportionately affecting younger individuals with a high potential for metastasis. Research has shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) and its ligands exhibit protective effects against melanoma. As a transcription factor, PPAR-γ is crucial in functions like fatty acid storage and glucose metabolism. Activation of PPAR-γ promotes lipid uptake and enhances sensitivity to insulin. In many cases, it also inhibits the growth of cancer cell lines, like breast, gastric, lung, and prostate cancer. In melanoma, PPAR-γ regulates cell proliferation, differentiation, apoptosis, and survival. During tumorigenesis, it controls metabolic changes and the immunogenicity of stromal cells. PPAR-γ agonists can target hypoxia-induced angiogenesis in tumor therapy, but their effects on tumors can be suppressive or promotional, depending on the tumor environment. Published data show that PPAR-γ-targeting agents can be effective in specific groups of patients, but further studies are needed to understand lesser-known biological effects of PPAR-γ and address the existing safety concerns. This review provides a summary of the current understanding of PPAR-γ and its involvement in melanoma.
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Affiliation(s)
- Vladimir Sobolev
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
| | - Ekaterina Tchepourina
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
| | - Anna Soboleva
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
| | - Elena Denisova
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
- Moscow Center of Dermatovenerology and Cosmetology, Moscow 119071, Russia
| | - Irina Korsunskaya
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
| | - Alexandre Mezentsev
- Laboratory of Physicochemical and Genetic Problems in Dermatology, Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow 109029, Russia; (V.S.); (E.T.); (A.S.); (E.D.); (I.K.)
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Liang SJ, Wang K, Mao DB, Xie LW, Zhu DJ. Inhibition of the Wnt/β‑catenin signaling pathway and SOX9 by XAV939 did not alleviate inflammation in a dextran sulfate sodium‑induced ulcerative colitis model. Exp Ther Med 2025; 29:24. [PMID: 39650775 PMCID: PMC11619566 DOI: 10.3892/etm.2024.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/12/2024] [Indexed: 12/11/2024] Open
Abstract
The Wnt/β-catenin signaling pathway has been reported to be hyperactivated during the pathogenesis of ulcerative colitis (UC). The present study aimed to explore the therapeutic efficacy of the Wnt/β-catenin signaling inhibitor XAV939 in mitigating UC symptoms. Utilizing a dextran sulfate sodium (DSS)-induced UC mouse model, the present study aimed to evaluate the impact of XAV939 on intestinal morphology through hematoxylin and eosin staining and to measure the expression levels of critical proteins in the Wnt/β-catenin signaling cascade. XAV939 did not exert a significant influence on the morphological features and inflammatory status of the intestinal epithelium. However, XAV939 was found to effectively suppress the Wnt/β-catenin signaling pathway and its downstream target SOX9. This suppression implied a reduction in the differentiation of intestinal stem cells into secretory cell progenitor cells. Additionally, XAV939 was ineffective at reversing the DSS-induced decrease in expression levels of Villin and peroxisome proliferator-activated receptor γ, which suggested that it did not facilitate the differentiation of intestinal absorptive cells. The present findings indicated that the Wnt/β-catenin signaling pathway may not be the predominant mechanism in the pathogenesis of DSS-induced UC.
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Affiliation(s)
- Shao-Jie Liang
- Maternal and Children's Health Research Institute, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, Guangdong 528300, P.R. China
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Kun Wang
- Maternal and Children's Health Research Institute, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, Guangdong 528300, P.R. China
| | - Da-Bin Mao
- Maternal and Children's Health Research Institute, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, Guangdong 528300, P.R. China
| | - Li-Wei Xie
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong 510075, P.R. China
| | - Da-Jian Zhu
- Maternal and Children's Health Research Institute, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, Guangdong 528300, P.R. China
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Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, Jonkisz A, Lebioda A, Adamiec-Mroczek J, Małodobra-Mazur M, Dobosz T. PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments. Biomolecules 2024; 14:786. [PMID: 39062500 PMCID: PMC11275227 DOI: 10.3390/biom14070786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Affiliation(s)
- Anna Skoczyńska
- Department of Internal and Occupational Medicine and Hypertension, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Monika Ołdakowska
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Agnieszka Dobosz
- Department of Basic Medical Sciences and Immunology, Division of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland
| | - Rajmund Adamiec
- Department of Diabetology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
- Department of Internal Medicine, Faculty of Medical and Technical Sciences, Karkonosze University of Applied Sciences, Lwówiecka 18, 58-506 Jelenia Góra, Poland
| | - Sofya Gritskevich
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Anna Jonkisz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Arleta Lebioda
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Joanna Adamiec-Mroczek
- Department of Ophthalmology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Tadeusz Dobosz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
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Robinson JW, Martin R, Ozawa M, Elwenspoek MMC, Redaniel MT, Kurian K, Ben-Shlomo Y. Use of drugs for hyperlipidaemia and diabetes and risk of primary and secondary brain tumours: nested case-control studies using the UK Clinical Practice Research Datalink (CPRD). BMJ Open 2024; 14:e072026. [PMID: 38336454 PMCID: PMC10860117 DOI: 10.1136/bmjopen-2023-072026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 12/05/2023] [Indexed: 02/12/2024] Open
Abstract
OBJECTIVES Previous studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records from the UK Clinical Practice Research Datalink (CPRD). DESIGN We conducted two nested case-control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication. SETTING Adults older than 18 years registered with a general practitioner in the UK contributing data to CPRD. RESULTS We identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours. CONCLUSIONS Longer exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.
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Affiliation(s)
- Jamie W Robinson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Richard Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Department of Population Health Sciences, University of Bristol Medical School, Bristol, UK
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, UK
| | - Mio Ozawa
- Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Martha Maria Christine Elwenspoek
- Department of Population Health Sciences, University of Bristol Medical School, Bristol, UK
- National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, Univeristy of Bristol, Bristol, UK
| | - Maria Theresa Redaniel
- Department of Population Health Sciences, University of Bristol Medical School, Bristol, UK
- National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, Univeristy of Bristol, Bristol, UK
| | - Kathreena Kurian
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Brain Tumour Research Centre, University of Bristol, Bristol, UK
| | - Yoav Ben-Shlomo
- Department of Population Health Sciences, University of Bristol Medical School, Bristol, UK
- National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, Univeristy of Bristol, Bristol, UK
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Holani R, Rathnayaka C, Blyth GA, Babbar A, Lahiri P, Young D, Dufour A, Hollenberg MD, McKay DM, Cobo ER. Cathelicidins Induce Toll-Interacting Protein Synthesis to Prevent Apoptosis in Colonic Epithelium. J Innate Immun 2022; 15:204-221. [PMID: 36116427 PMCID: PMC10643900 DOI: 10.1159/000526121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 06/27/2022] [Indexed: 11/17/2023] Open
Abstract
Cathelicidin peptides secreted by leukocytes and epithelial cells are microbicidal but also regulate pathogen sensing via toll-like receptors (TLRs) in the colon by mechanisms that are not fully understood. Herein, analyses with the attaching/effacing pathogen Citrobacter rodentium model of colitis in cathelicidin-deficient (Camp-/-) mice, and colonic epithelia demonstrate that cathelicidins prevent apoptosis by sustaining post-transcriptional synthesis of a TLR adapter, toll-interacting protein (TOLLIP). Cathelicidins induced phosphorylation-activation of epidermal growth factor receptor (EGFR)-kinase, which phosphorylated-inactivated miRNA-activating enzyme Argonaute 2 (AGO2), thus reducing availability of the TOLLIP repressor miRNA-31. Cathelicidins promoted stability of TOLLIP protein via a proteosome-dependent pathway. This cathelicidin-induced TOLLIP upregulation prevented apoptosis in the colonic epithelium by reducing levels of caspase-3 and poly (ADP-ribose) polymerase (PARP)-1 in response to the proinflammatory cytokines, interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Further, Camp-/- colonic epithelial cells were more susceptible to apoptosis during C. rodentium infection than wild-type cells. This antiapoptotic effect of cathelicidins, maintaining epithelial TOLLIP protein in the gut, provides insight into cathelicidin's ability to regulate TLR signaling and prevent exacerbated inflammation.
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Affiliation(s)
- Ravi Holani
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Chathurika Rathnayaka
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Graham A.D. Blyth
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Anshu Babbar
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Priyoshi Lahiri
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Daniel Young
- Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Antoine Dufour
- Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Morley D. Hollenberg
- Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Derek M. McKay
- Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Eduardo R. Cobo
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms23073813. [PMID: 35409177 PMCID: PMC8998922 DOI: 10.3390/ijms23073813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/11/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered in cancer therapy for their inhibitory effect on cyclooxygenase-2 (COX-2), which is overexpressed in most cancers. However, we found that NSAIDs as ligands of peroxisome proliferator-activated receptor-γ (PPARγ)-induced apoptosis independent of the COX-2 inhibition, and the process was mediated through activation of proline dehydrogenase/proline oxidase (PRODH/POX)-dependent generation of reactive oxygen species (ROS). This mitochondrial enzyme converts proline to ∆1-pyrroline-5-carboxylate (P5C) during which ATP or ROS is generated. To confirm the role of PRODH/POX in the mechanism of NSAID-induced apoptosis we obtained an MCF7 CRISPR/Cas9 PRODH/POX knockout breast cancer cell model (MCF7POK-KO). Interestingly, the studied NSAIDs (indomethacin and diclofenac) in MCF7POK-KO cells contributed to a more pronounced pro-apoptotic phenotype of the cells than in PRODH/POX-expressing MCF7 cells. The observed effect was independent of ROS generation, but it was related to the energetic disturbances in the cells as shown by an increase in the expression of AMPKα (sensor of cell energy status), GLUD1/2 (proline producing enzyme from glutamate), prolidase (proline releasing enzyme), PPARδ (growth supporting transcription factor) and a decrease in the expression of proline cycle enzymes (PYCR1, PYCRL), mammalian target of rapamycin (mTOR), and collagen biosynthesis (the main proline utilizing process). The data provide evidence that the studied NSAIDs induce PRODH/POX-dependent and independent apoptosis in MCF7 breast cancer cells.
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MicroRNA hsa-miR-657 promotes retinoblastoma malignancy by inhibiting peroxisome proliferator-activated receptor alpha expression. Anticancer Drugs 2022; 33:478-488. [PMID: 35324527 DOI: 10.1097/cad.0000000000001308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Retinoblastoma is a familial inherited embryonic neuroretinal malignancy with a low survival rate and poor prognosis. Our study aimed to evaluate the potential interaction between microRNA miR-657 and the peroxisome proliferator-activated receptor alpha (PPARA) in retinoblastoma. Expression of miR-657 and PPARA was analyzed in retinoblastoma tissues and cells using RT-qPCR. Cell proliferation, apoptosis, and migration were measured in retinoblastoma cell lines, and xenografting experiments were performed using nude mice. Our study showed that miR-657 expression was markedly increased, whereas that of PPARA was markedly decreased in retinoblastoma. Additionally, PPARA knockdown enhanced the development of retinoblastoma. miR-657 enhanced the retinoblastoma tumorigenesis by directly inhibiting PPARA expression, suggesting that PPARA targeting by miR-657 facilitates retinoblastoma development by enhancing cell growth. This study provides novel insights into the miR-657- and PPARA-mediated mechanisms underlying retinoblastoma progression and suggests that the interaction between miR-657 and PPARA may serve as an effective target for therapeutic intervention.
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Kazberuk A, Chalecka M, Palka J, Surazynski A. Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis. Int J Mol Sci 2022; 23:ijms23031510. [PMID: 35163433 PMCID: PMC8835909 DOI: 10.3390/ijms23031510] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX–PPARγ axis can be considered a novel approach for breast cancer treatment.
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CB13, a novel PPARγ ligand, overcomes radio-resistance via ROS generation and ER stress in human non-small cell lung cancer. Cell Death Dis 2020; 11:848. [PMID: 33051435 PMCID: PMC7555888 DOI: 10.1038/s41419-020-03065-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 08/20/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-known therapeutic target for type 2 diabetes as well as is a potential target for effective anti-cancer drug, since PPARγ ligands such as ciglitazone (Cig) frequently cause cell death in many types of cancer cells and suppress tumor growth. However, many cancer patients acquire chemo-resistance or radio-resistance after chemo or radiotherapy, and it is still unclear. In the difficulty of well-known anti-cancer drugs, we developed a novel PPARγ agonist CB13 (1-benzyl-5-(4-methylphenyl) pyrido [2,3-d]pyrimidine-2,4(1H,3H)-dione) and investigated the anti-cancer effect and cell death mechanism on human non-small cell lung cancer (NSCLC) cells. With anti-cancer effect of Cig, CB13 also causes inhibition of cell growth by decreasing cell viability, increasing the release of LDH, and increasing caspase-3, and caspase-9 activities. CB13 generates reactive oxygen species (ROS) and causes cell death via ER stress in NSCLC and radio-resistant NSCLC cells (A549R and H460R), and a combination of CB13 and radiation induces greater ER stress and cell death when compared to CB13 alone. Taken together, our results suggest that a combination of CB13 and radiation may overcome radio-resistance caused by radiotherapy.
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12
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Kazberuk A, Zareba I, Palka J, Surazynski A. A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor. Pharmacol Rep 2020; 72:1152-1160. [PMID: 32710395 PMCID: PMC7550302 DOI: 10.1007/s43440-020-00140-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/19/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
Although pharmaco-epidemiological studies provided evidence for the anticancer potential of non-steroidal anti-inflammatory drugs (NSAIDs), the mechanism of their anti-cancer activity is not known. Several lines of evidence suggest that proline dehydrogenase/proline oxidase (PRODH/POX) may represent a target for NSAIDs-dependent anti-cancer activity. PRODH/POX catalyzes conversion of proline into Δ1-pyrroline-5-carboxylate releasing ATP or reactive oxygen species for autophagy/apoptosis. Since NSAIDs are ligands of peroxisome proliferator-activated receptor (PPARs) and PPARs are implicated in PRODH/POX-dependent apoptosis we provided a hypothesis on the mechanism of NSAIDs-induced apoptosis in cancer cells.
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Affiliation(s)
- Adam Kazberuk
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Ilona Zareba
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Jerzy Palka
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Arkadiusz Surazynski
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
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13
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Oh I, Raymundo B, Jung SA, Kim HJ, Park J, Kim C. Extremely
Low‐Frequency
Electromagnetic Field Altered
PPARγ
and
CCL2
Levels and Suppressed
CD44
+
/
CD24
−
Breast Cancer Cells Characteristics. B KOREAN CHEM SOC 2020. [DOI: 10.1002/bkcs.12072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- In‐Rok Oh
- College of Life Sciences and BiotechnologyKorea University Seoul 136‐701 Korea
| | - Bernardo Raymundo
- College of Life Sciences and BiotechnologyKorea University Seoul 136‐701 Korea
| | - Sung A Jung
- College of Life Sciences and BiotechnologyKorea University Seoul 136‐701 Korea
| | - Hyun Jung Kim
- College of Life Sciences and BiotechnologyKorea University Seoul 136‐701 Korea
| | - Jung‐Keug Park
- Dongguk University Biomedi CampusDongguk University Goyang Korea
| | - Chan‐Wha Kim
- College of Life Sciences and BiotechnologyKorea University Seoul 136‐701 Korea
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14
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Decara J, Rivera P, López-Gambero AJ, Serrano A, Pavón FJ, Baixeras E, Rodríguez de Fonseca F, Suárez J. Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases. Front Pharmacol 2020; 11:730. [PMID: 32536865 PMCID: PMC7266982 DOI: 10.3389/fphar.2020.00730] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 05/01/2020] [Indexed: 12/17/2022] Open
Abstract
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.
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Affiliation(s)
- Juan Decara
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Patricia Rivera
- Departamento de Endocrinología, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Antonio Jesús López-Gambero
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Antonia Serrano
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Francisco Javier Pavón
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) and UGC del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Elena Baixeras
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, IBIMA, Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Juan Suárez
- UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
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15
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Costantini L, Molinari R, Farinon B, Merendino N. Retinoic Acids in the Treatment of Most Lethal Solid Cancers. J Clin Med 2020; 9:E360. [PMID: 32012980 PMCID: PMC7073976 DOI: 10.3390/jcm9020360] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.
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Affiliation(s)
- Lara Costantini
- Department of Ecological and Biological Sciences (DEB), Tuscia University, Largo dell’Università snc, 01100 Viterbo, Italy
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16
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Ismail NI, Othman I, Abas F, H Lajis N, Naidu R. Mechanism of Apoptosis Induced by Curcumin in Colorectal Cancer. Int J Mol Sci 2019; 20:E2454. [PMID: 31108984 PMCID: PMC6566943 DOI: 10.3390/ijms20102454] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 04/20/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage of chemo drugs such as FOLFOX and FOLFIRI, surgery and radiotherapy, which are usually accompanied with major side effects, are rarely cured along with poor survival rate and at higher recurrence outcome. This trigger the needs of exploring new natural compounds with anti-cancer properties which possess fewer side effects. Curcumin, a common spice used in ancient medicine was found to induce apoptosis by targeting various molecules and signaling pathways involved in CRC. Disruption of the homeostatic balance between cell proliferation and apoptosis could be one of the promoting factors in colorectal cancer progression. In this review, we describe the current knowledge of apoptosis regulation by curcumin in CRC with regard to molecular targets and associated signaling pathways.
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Affiliation(s)
- Nor Isnida Ismail
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
- UniKL MESTECH, A1-1 Jalan TKS1, Taman Kajang Sentral, 43000 Kajang, Malaysia.
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia, UPM, 43400 Serdang, Malaysia.
- Department of Food Science, Faculty of Food Science and Technology, University Putra Malaysia, UPM, 434000 Serdang, Malaysia.
| | - Nordin H Lajis
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia, UPM, 43400 Serdang, Malaysia.
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
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17
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Liu QQ, Wang P, He QJ, Ma R, Lee SC. PPARγ promotes diabetes‐associated centrosome amplification via increasing the expression of SKA1 directly at the transcriptional level. J Cell Physiol 2019; 234:20694-20703. [DOI: 10.1002/jcp.28674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 03/09/2019] [Accepted: 03/19/2019] [Indexed: 12/29/2022]
Affiliation(s)
- Qin Qin Liu
- Department of Biology, School of Life Sciences Shanxi University Taiyuan Shanxi PR China
| | - Pu Wang
- Department of Biology, School of Life Sciences Shanxi University Taiyuan Shanxi PR China
| | - Qin Ju He
- Department of Biology, School of Life Sciences Shanxi University Taiyuan Shanxi PR China
| | - Ronald Ma
- Department of Medicine and Therapeutics Chinese University of Hong Kong Shatin Hong Kong SAR PR China
| | - Shao Chin Lee
- Department of Biology, School of Life Sciences Shanxi University Taiyuan Shanxi PR China
- Department of Biology, School of Life Sciences Jiangsu Normal University Xuzhou Jiangsu PR China
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18
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Ong AL, Ramasamy TS. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev 2018; 43:64-80. [PMID: 29476819 DOI: 10.1016/j.arr.2018.02.004] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 01/23/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022]
Abstract
Regulatory role of Sirtuin 1 (SIRT1), one of the most extensively studied members of its kind in histone deacetylase family in governing multiple cellular fates, is predominantly linked to p53 activity. SIRT1 deacetylates p53 in a NAD+-dependent manner to inhibit transcription activity of p53, in turn modulate pathways that are implicated in regulation of tissue homoeostasis and many disease states. In this review, we discuss the role of SIRT1-p53 pathway and its regulatory axis in the cellular events which are implicated in cellular aging, cancer and reprogramming. It is noteworthy that these cellular events share few common regulatory pathways, including SIRT1-p53-LDHA-Myc, miR-34a,-Let7 regulatory network, which forms a positive feedback loop that controls cell cycle, metabolism, proliferation, differentiation, epigenetics and many others. In the context of aging, SIRT1 expression is reduced as a protective mechanism against oncogenesis and for maintenance of tissue homeostasis. Interestingly, its activation in aged cells is evidenced in response to DNA damage to protect the cells from p53-dependent apoptosis or senescence, predispose these cells to neoplastic transformation. Importantly, the dual roles of SIRT1-p53 axis in aging and tumourigenesis, either as tumour suppressor or tumour promoter are determined by SIRT1 localisation and type of cells. Conceptualising the distinct similarity between tumorigenesis and cellular reprogramming, this review provides a perspective discussion on involvement of SIRT1 in improving efficiency in the induction and maintenance of pluripotent state. Further research in understanding the role of SIRT1-p53 pathway and their associated regulators and strategies to manipulate this regulatory axis very likely foster the development of therapeutics and strategies for treating cancer and aging-associated degenerative diseases.
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19
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Li Q, Peng YS, Chen PJ, Wang ML, Cao C, Xiong H, Zhang J, Chen MH, Peng XB, Zeng K. Peroxisome proliferator-activated receptor-γ agonist-mediated inhibition of cell growth is independent of apoptosis in human epidermoid carcinoma A431 cells. Oncol Lett 2018; 15:6578-6584. [PMID: 29725405 DOI: 10.3892/ol.2018.8136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 08/23/2017] [Indexed: 12/26/2022] Open
Abstract
Evidence suggests that peroxisome proliferator activated receptor-γ (PPAR-γ) acts as a tumor suppressor in multiple types of cancer; however, the role of action of PPAR-γ on human epidermoid carcinoma is unclear. The present study investigated the effects of a PPAR-γ agonist, rosiglitazone, on human epidermoid carcinoma cell growth using the A431 cell line. The effects of rosiglitazone on cell viability and proliferation were evaluated with MTS and [3H] thymidine incorporation assays. The effects of rosiglitazone on the cell cycle and apoptosis were analyzed by flow cytometry, and western blotting. It was identified that rosiglitazone inhibited A431 cell proliferation in a dose-dependent manner, increased the proportion of cells in the G1 phase, but did not affect apoptosis. Consistently, there was a significant decrease in the expression of cell proliferation-associated proteins, including cyclin D1, cyclin-dependent kinase (Cdk)2 and Cdk4 in A431 cells treated with rosiglitazone. This decrease was rescued by a selective antagonist of PPAR-γ or specific PPAR-γ small interfering RNAs. However, the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2 associated X protein, which is associated with cell apoptosis, was not affected by these treatments. The data of the present study suggest that the PPAR-γ agonist rosiglitazone inhibits human epidermoid carcinoma cell growth through regulating the expression of the cell cycle-associated proteins, and that this effect is independent of apoptosis.
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Affiliation(s)
- Qian Li
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yu-Sheng Peng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ping-Jiao Chen
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Meng-Lei Wang
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Can Cao
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hao Xiong
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jing Zhang
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ming-Hua Chen
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xue-Biao Peng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Kang Zeng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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20
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Yun SH, Roh MS, Jeong JS, Park JI. Peroxisome proliferator-activated receptor γ coactivator-1α is a predictor of lymph node metastasis and poor prognosis in human colorectal cancer. Ann Diagn Pathol 2017; 33:11-16. [PMID: 29566941 DOI: 10.1016/j.anndiagpath.2017.11.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/09/2017] [Accepted: 11/09/2017] [Indexed: 11/28/2022]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) expression levels are correlated with clinical outcome in breast cancer. However, the potential biological and clinical significance of PPARγ and PGC-1α in colorectal cancer remains unknown. Here we investigated PPARγ and PGC-1α expression in colorectal cancer, and the associations of these expression levels with clinicopathological features. We also evaluated the roles of PPARγ and PGC-1α as prognostic factors in colorectal cancer. We performed immunohistochemical analysis to investigate PPARγ and PGC-1α expression in human colorectal cancer tissues and adjacent normal tissues from 108 primary colorectal cancer patients. We then examined how these expression levels correlated with clinicopathological features. Using the Kaplan-Meier method, we evaluated 3-year disease-free survival (DFS) and overall survival (OS) in patients with tumors expressing different levels of PPARγ and PGC-1α. Our results revealed that PPARγ expression was not significantly correlated with age at surgery, gender, differentiation, depth of infiltration, relapse, or TNM stage. Additionally, PGC-1α expression was not significantly correlated with age at surgery, differentiation, depth of infiltration, relapse, or TNM stage. However, PGC-1α expression was significantly correlated with nodal metastasis (p=0.020). Survival analysis demonstrated reduced OS in the PGC-1α-positive group compared to the PGC-1α-negative group (p=0.03). Our present findings suggest that PGC-1α may be useful for predicting nodal metastasis, and may represent a biomarker for poor prognosis in colorectal cancer.
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Affiliation(s)
- Seong-Hoon Yun
- Department of Biochemistry, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-Gu, Busan 49201, Republic of Korea
| | - Mee-Sook Roh
- Department of Pathology, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-Gu, Busan 49201, Republic of Korea
| | - Jin-Sook Jeong
- Department of Pathology, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-Gu, Busan 49201, Republic of Korea
| | - Joo-In Park
- Department of Biochemistry, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-Gu, Busan 49201, Republic of Korea.
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21
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González N, Prieto I, del Puerto-Nevado L, Portal-Nuñez S, Ardura JA, Corton M, Fernández-Fernández B, Aguilera O, Gomez-Guerrero C, Mas S, Moreno JA, Ruiz-Ortega M, Sanz AB, Sanchez-Niño MD, Rojo F, Vivanco F, Esbrit P, Ayuso C, Alvarez-Llamas G, Egido J, García-Foncillas J, Ortiz A, Diabetes Cancer Connect Consortium. 2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications. Oncotarget 2017; 8:18456-18485. [PMID: 28060743 PMCID: PMC5392343 DOI: 10.18632/oncotarget.14472] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/26/2016] [Indexed: 02/06/2023] Open
Abstract
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.
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Affiliation(s)
- Nieves González
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Isabel Prieto
- Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Laura del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Sergio Portal-Nuñez
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Juan Antonio Ardura
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Corton
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Oscar Aguilera
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Sebastián Mas
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | | | - Ana Belen Sanz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
| | | | - Federico Rojo
- Pathology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Pedro Esbrit
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Ayuso
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesús García-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Alberto Ortiz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
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22
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Vella V, Nicolosi ML, Giuliano S, Bellomo M, Belfiore A, Malaguarnera R. PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis. Front Endocrinol (Lausanne) 2017; 8:31. [PMID: 28275367 PMCID: PMC5319972 DOI: 10.3389/fendo.2017.00031] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/06/2017] [Indexed: 12/13/2022] Open
Abstract
It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.
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Affiliation(s)
- Veronica Vella
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Stefania Giuliano
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Maria Bellomo
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore,
| | - Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Park H, Ko SH, Lee JM, Park JH, Choi YH. Troglitazone Enhances the Apoptotic Response of DLD-1 Colon Cancer Cells to Photodynamic Therapy. Yonsei Med J 2016; 57:1494-9. [PMID: 27593880 PMCID: PMC5011284 DOI: 10.3349/ymj.2016.57.6.1494] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 04/05/2016] [Accepted: 04/13/2016] [Indexed: 11/27/2022] Open
Abstract
PURPOSE The aim of this study was to investigate whether the peroxisomal proliferator-activated receptor gamma (PPARγ) ligand troglitazone in combination with photodynamic therapy (PDT) enhances the apoptotic response of DLD-1 colon cancer cells. MATERIALS AND METHODS The effects of troglitazone, PDT, and troglitazone in combination with PDT on cell viability and apoptosis were assessed in DLD-1 cells. Cell viability and proliferation were evaluated using the tetrazolium-based MTT assay, and apoptosis was evaluated via cell staining with propidium iodide (PI) and annexin V-FITC. The levels of pro-caspase-3 were measured via Western blot analyses. RESULTS Treatment of troglitazone and PDT induced the growth retardation and cell death of DLD-1 cells in a dose-dependent manner, respectively. The combination treatment significantly suppressed cell growth and increased the apoptotic response of DLD-1 and resulted in apoptosis rather than necrosis, as shown by PI/annexin V staining and degradation of procaspase-3. CONCLUSION These results document the anti-proliferative and apoptotic activities of PDT in combination with the PPARγ ligand troglitazone and provide a strong rationale for testing the therapeutic potential of combination treatment in colon cancer.
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Affiliation(s)
- Hyunju Park
- Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea
| | - Si Hwan Ko
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Myun Lee
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Jeon Han Park
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Youn Hee Choi
- Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
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Wang F, Liu Y, Bi Z. Pioglitazone inhibits growth of human retinoblastoma cells via regulation of NF-κB inflammation signals. J Recept Signal Transduct Res 2016; 37:94-99. [PMID: 27133446 DOI: 10.3109/10799893.2016.1171341] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES We aimed to study the antitumor effects of the PPARγ agonist pioglitazone on human retinoblastoma. METHODS The effects of pioglitazone on cell proliferation and apoptosis of the human retinoblastoma Y79 cells were investigated by MTT assay and Hoechst 33258 staining assay. The apoptosis related protein levels were detected by western blot. Inflammationary factors analysis was evaluated by western blot and ELISA. The effect of pioglitazone on nuclear factor-kappa B (NF-κB)-dependent reporter gene transcription induced by LPS was analyzed by NF-κB-luciferase assay. Then human retinoblastoma Y79 cells were subcutaneously transplanted in BALB/c nude mice and the animals were treated with pioglitazone to verify its antitumor effect in vivo. RESULTS Our data revealed that pioglitazone suppressed the viability of Y79 cells dose- and time-dependently and induced apoptosis in Y79 cells in vitro. Molecular biology analysis found that pioglitazone could affect the apoptosis and inflammation related signal via modulating the activity of NF-κB signal. Also we found that pioglitazone could markedly reduce the growth of Y79 cells transplanted into the mice without causing significant side effects. CONCLUSIONS Our results suggested that pioglitazone demonstrated antitumor activity against the human retinoblastoma Y79 cells by inhibiting cell growth, inducing apoptosis and modulating NF-κB pathway, and thus delayed tumor growth in vivo.
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Affiliation(s)
- Fengyun Wang
- a Department of Ophthalmology , The First Affiliated Hospital, Henan University of Science and Technology , Luoyang , Henan , PR China
| | - Yang Liu
- b Department of Stomatology, Nanfang Hospital, Southern Medical University , Guangzhou , Guangdong Province , PR China
| | - Zhenyu Bi
- c Department of Anatomy, Key Laboratory of Medical Biomechanics of Guangdong Province , Southern Medical University , Guangzhou , Guangdong Province , PR China
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Cao X, He L, Li Y. Effects of PPARγ agonistrosiglitazone on human retinoblastoma cell in vitro and in vivo. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:12549-12556. [PMID: 26722443 PMCID: PMC4680388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 09/25/2015] [Indexed: 06/05/2023]
Abstract
The aim of the study was to evaluate the antitumor effects of the PPARγ agonist rosiglitazone on the human retinoblastoma. The cell biological behavior was detected, specifically, the effects of rosiglitazone on cell viability and apoptosis of the human retinoblastoma Y79 cells were investigated by MTT assay and Hochest 33258 staining and the migration assay showed that rosiglitazone blocked the invasion and migration of the carcinoma cells through the reconstituted extracellular matrix (Matrigel). The effect of rosiglitazone on NF-κB-dependent reporter gene transcription induced by LPS was analyzed by NF-κB-luciferase assay. Then human retinoblastoma Y79 cells were subcutaneously transplanted in BALB/c nude mice, and the animals were treated with rosiglitazone (20 mg/kg, 40 mg/kg, and 80 mg/kg) to verify its anti-tumor effect in vivo. Rosiglitazone suppressed the viability of Y79 cells dose- and time-dependently and induced apoptosis in Y79 cells in vitro. Molecular biology analysis found that rosiglitazone could modulate the proliferative and apoptosis related signal, reduce NF-κB-dependent reporter gene transcription induced by LPS. Rosiglitazone markedly reduced the growth of Y79 cells transplanted into the mice without causing significant side effects. Our results suggested that rosiglitazone demonstrated antitumor activity against the human retinoblastoma Y79 cells by inhibiting cell growth, inducing apoptosis and inhibiting metastasis and invasion in vitro and delaying tumor growth in vivo.
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Affiliation(s)
- Xianyong Cao
- Department of Ophthalmology, The Third Affiliated Hospital of Xinxiang Medical University, Eye Hospital of Xinxiang Medical University Xinxiang 453000, Henan Province, China
| | - Lin He
- Department of Ophthalmology, The Third Affiliated Hospital of Xinxiang Medical University, Eye Hospital of Xinxiang Medical University Xinxiang 453000, Henan Province, China
| | - Yanhua Li
- Department of Ophthalmology, The Third Affiliated Hospital of Xinxiang Medical University, Eye Hospital of Xinxiang Medical University Xinxiang 453000, Henan Province, China
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26
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Song M, Tian X, Lu M, Zhang X, Ma K, Lv Z, Wang Z, Hu Y, Xun C, Zhang Z, Wang S. Genistein exerts growth inhibition on human osteosarcoma MG-63 cells via PPARγ pathway. Int J Oncol 2015; 46:1131-40. [PMID: 25586304 DOI: 10.3892/ijo.2015.2829] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 12/03/2014] [Indexed: 11/06/2022] Open
Abstract
The peroxisome proliferator-activated receptor γ (PPARγ) is emerging as an important regulator in various metabolic processes of cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities, particularly, in cancer prevention. However, the mechanisms by which genistein elicits its growth inhibiting effects in osteosarcoma (OS) MG-63 cells have not been extensively elucidated. MG-63 cells were treated for 2 days with various concentrations of genistein and/or GW9662 (a selective antagonist of PPARγ). The effect of different drugs on cell viability was determined by Cell Counting Kit-8 (CCK-8). The assay of cell proliferation was performed using 5-ethynyl-2'-deoxyuridine (EdU). The changes of apoptosis and cell cycle progression were detected by flow cytometry experiments. The protein expression of PPARγ pathway (PPARγ, PTEN, BCL-2, Survivin, P21WAF1/CIP1 and Cyclin B1) was determined by western blot analysis. The expression of PPARγ and PTEN mRNA was detected by real-time quantitative RT-PCR analysis. We report that genistein caused OS cell growth inhibition. We found that the PPARγ expression in OS cells increased after genistein treatment. Further studies on the mechanisms of genistein revealed a series of cell growth changes related to the PPARγ pathway; while cell cycle changes can be reversed by GW9662. Genistein plays an important role in preventing OS cell growth, which can impede the OS cell cycle as a non-toxic activator of PPARγ, providing novel insights into the mechanisms of the therapeutic activities of genistein.
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Affiliation(s)
- Mingzhi Song
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xiliang Tian
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Ming Lu
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xianbin Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Kai Ma
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Zhichao Lv
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Zhenxing Wang
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Yang Hu
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Chong Xun
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Zhen Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Shouyu Wang
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Abstract
AIMS This review is aimed at highlighting the potential mitogenic/tumour growth-promoting or antimitogenic/tumour growth-inhibiting effects of the main antihyperglycaemic drug classes. METHODS We review and discuss the most current studies evaluating the association between antidiabetic medications used in clinical practice and malignancies as described so far. RESULTS Metformin seems to be the only antidiabetic drug to exert protective effects both on monotherapy and also when combined with other oral antidiabetic drugs or insulins in several site-specific cancers. In contrast, several other drug classes may increase cancer risk. Some reason for concern remains regarding sulphonylureas and also the incretin-based therapies regarding pancreas and thyroid cancers and the sodium glucose cotransporter-2 inhibitors as well as pioglitazone regarding bladder cancer. The majority of meta-analyses suggest that there is no evidence for a causal relationship between insulin glargine and elevated cancer risk, although the studies have been controversially discussed. For α-glucosidase inhibitors and glinides, neutral or only few data upon cancer risk exist. CONCLUSION Although the molecular mechanisms are not fully understood, a potential risk of mitogenicity and tumour growth promotion cannot be excluded in case of several antidiabetic drug classes. However, more large-scale, randomized, well-designed clinical studies with especially long follow-up time periods are needed to get reliable answers to these safety issues.
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Affiliation(s)
- Stefan Z Lutz
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Harald Staiger
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany Division of Nutritional and Preventive Medicine, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
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Abstract
Thyroid carcinoma is the most common endocrine malignancy, and its incidence is continuing to increase. Most thyroid carcinomas contain one of several known driver mutations, such as the Val600Glu substitution in B-Raf, Ras mutations, RET gene fusions, or PAX8-PPARG gene fusions. The PAX8-PPARG gene fusion results in the production of a Pax-8-PPAR-γ fusion protein (PPFP), which is found in approximately one-third of follicular thyroid carcinomas, as well as some follicular-variant papillary thyroid carcinomas. In vitro and in vivo evidence indicates that PPFP is an oncoprotein. Although specific mechanisms of action remain to be defined, PPFP is considered to act as a dominant-negative inhibitor of wild-type PPAR-γ and/or as a unique transcriptional activator of subsets of PPAR-γ-responsive and Pax-8-responsive genes. Detection of the fusion transcript in thyroid nodule biopsy specimens can aid clinical decision-making when cytological findings are indeterminate. The PPAR-γ agonist pioglitazone is highly therapeutic in a transgenic mouse model of PPFP-positive thyroid carcinoma, suggesting that PPAR-γ agonists might be beneficial in patients with PPFP-positive thyroid carcinomas.
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Affiliation(s)
- Priyadarshini Raman
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5560 MSRB-2, SPC 5678, 1150 West Medical Drive, Ann Arbor, MI 48109, USA
| | - Ronald J Koenig
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5560 MSRB-2, SPC 5678, 1150 West Medical Drive, Ann Arbor, MI 48109, USA
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Ninomiya I, Yamazaki K, Oyama K, Hayashi H, Tajima H, Kitagawa H, Fushida S, Fujimura T, Ohta T. Pioglitazone inhibits the proliferation and metastasis of human pancreatic cancer cells. Oncol Lett 2014; 8:2709-2714. [PMID: 25364454 PMCID: PMC4214501 DOI: 10.3892/ol.2014.2553] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 09/08/2014] [Indexed: 01/03/2023] Open
Abstract
Proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that acts as a transcription factor in several types of tissue. PPAR-γ ligands are known to inhibit numerous cancer cell processes, including pancreatic cancer cell proliferation through terminal differentiation. Previous studies concerning the inhibitory effect of PPAR-γ ligands derived from thiazolidinediones (TZDs) on the metastatic potential of cancer cells have been reported. The present study aimed to investigate whether pioglitazone, a prescription TZD class drug and a ligand of PPAR-γ, inhibits the proliferation and metastasis of pancreatic cancer cells. The inhibitory effect of pioglitazone on the proliferation of the Capan-1, Aspc-1, BxPC-3, PANC-1 and MIApaCa-2 pancreatic cancer cell lines was analyzed. Alterations in carcinoembryonic antigen (CEA), interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) mRNA expression levels subsequent to pioglitazone treatment were examined in BxPC-3 cells by quantitative reverse transcription polymerase chain reaction. In addition, whether the oral administration of pioglitazone prevents tumorigenesis and spontaneous BxPC-3 cell lymph node and lung metastases was investigated using a rectal xenograft model. Pioglitazone treatment resulted in the inhibition of proliferation in all five pancreatic cancer cell lines in vitro. Pioglitazone induced CEA mRNA expression, suppressed IL-8 and COX-2 mRNA expression in vitro, and inhibited BxPC-3 xenograft growth. Pioglitazone also reduced BxPC-3 cell lymph node and lung metastasis in the rectal xenograft model. These results suggest that pioglitazone treatment inhibited the proliferation and metastasis of pancreatic cancer cells through the induction of differentiation and the inhibition of angiogenesis-associated protein expression.
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Affiliation(s)
- Itasu Ninomiya
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Keisuke Yamazaki
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Katsunobu Oyama
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hironori Hayashi
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hidehiro Tajima
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hirohisa Kitagawa
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Sachio Fushida
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takashi Fujimura
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuo Ohta
- Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
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30
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Emerging roles of peroxisome proliferator-activated receptor gamma in cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Matsuura S, Kahyo T, Shinmura K, Iwaizumi M, Yamada H, Funai K, Kobayashi J, Tanahashi M, Niwa H, Ogawa H, Takahashi T, Inui N, Suda T, Chida K, Watanabe Y, Sugimura H. SGOL1 variant B induces abnormal mitosis and resistance to taxane in non-small cell lung cancers. Sci Rep 2013; 3:3012. [PMID: 24146025 PMCID: PMC3804856 DOI: 10.1038/srep03012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 10/02/2013] [Indexed: 01/21/2023] Open
Abstract
Mitosis is the most conspicuous cell cycle phase and Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation during mitosis. We studied the role of SGOL1 and its splice variants in non-small cell lung cancer (NSCLC) using 82 frozen NSCLC tissue samples. SGOL1-B expression was prevalent in smokers, in cases with a wild-type (WT) EGFR status, and in cases with the focal copy number amplification of genes that are known to be important for defining the biological behaviors of NSCLC. The overexpression of SGOL1-B1 in an NSCLC cell line induced aberrant chromosome missegregation, precociously separated chromatids, and delayed mitotic progression. A higher level of SGOL1-B mRNA was related to taxane resistance, while the forced downregulation of SGOL1-B increased the sensitivity to taxane. These results suggest that the expression of SGOL1-B causes abnormal mitosis and taxane resistance in NSCLC cells.
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Affiliation(s)
- Shun Matsuura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Tomoaki Kahyo
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kazuhito Funai
- First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Jun Kobayashi
- Thoracic Surgery, Shimada Municipal Hospital, 1200-5 Noda, Shimada, Shizuoka, 427-8502, Japan
| | - Masayuki Tanahashi
- Division of Thoracic Surgery, Respiratory Disease Center, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka, 433-8558, Japan
| | - Hiroshi Niwa
- Division of Thoracic Surgery, Respiratory Disease Center, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka, 433-8558, Japan
| | - Hiroshi Ogawa
- Division of Pathology, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka, 433-8558, Japan
| | - Takashi Takahashi
- Department of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kingo Chida
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Yoshinori Watanabe
- Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo, 113-0032, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
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Gu C, Gonzalez J, Zhang T, Kamel-Reid S, Wells RA. The aryl hydrocarbon receptor nuclear translocator (ARNT) modulates the antioxidant response in AML cells. Leuk Res 2013; 37:1750-6. [PMID: 24220583 DOI: 10.1016/j.leukres.2013.10.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 10/11/2013] [Accepted: 10/12/2013] [Indexed: 10/26/2022]
Abstract
We observed AML cell lines vary in their sensitivity to induction of apoptosis by troglitazone (TG), which induces apoptosis through the generation of intracellular reactive oxygen species (ROS). TG-resistant cell lines had increased abundance of ARNT transcripts and protein. Expression of ARNT in TG-sensitive cells made these cells resistant to both TG and daunorubicin. ARNT-expressing cells had increased expression of SOD2 and Nrf2 transcripts and elevated intracellular GSH concentration. Our results indicate that ARNT expression in AML cells augments antioxidant response and confers resistance to ROS inducers. This suggests ARNT may modulate ROS signaling and drug response in AML.
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Affiliation(s)
- Chunhong Gu
- The J. Douglas Crashley MDS Research Laboratory, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada
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Lin PC, Lin YJ, Lee CT, Liu HS, Lee JC. Cyclooxygenase-2 expression in the tumor environment is associated with poor prognosis in colorectal cancer patients. Oncol Lett 2013; 6:733-739. [PMID: 24137401 PMCID: PMC3789101 DOI: 10.3892/ol.2013.1426] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 06/18/2013] [Indexed: 12/31/2022] Open
Abstract
The development of colorectal cancer (CRC) is commonly accompanied by the overexpression of the cyclooxygenase-2 (COX-2) gene, with high levels being most common in early colorectal lesions. In the present study, we hypothesized that the expression of COX-2 in normal mucosa affects the expression of COX-2 in adjacent tumors. COX-2 protein expression levels were determined in tumor tissues and the adjacent normal mucosa of 49 paired clinical CRC specimens using western blotting and immunohistochemistry (IHC) staining. The majority of specimens exhibited an extremely low level of COX-2 expression in the tumor tissue and a markedly higher expression level in the adjacent normal tissue, however, high COX-2 expression in the tumor was shown to correlate with a high recurrence rate and poor overall survival. Of the nine CRC cell lines, HT29 showed consistently higher levels of COX-2 expression. Therefore, COX-2 expression in the normal tissue adjacent to the tumor may be involved in the tumorigenesis of CRC. These observations are likely to be useful in determining the significance of COX-2 expression in the tumorigenesis of CRC.
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Affiliation(s)
- Peng-Chan Lin
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, R.O.C
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Ohashi M, Oyama T, Putranto EW, Waku T, Nobusada H, Kataoka K, Matsuno K, Yashiro M, Morikawa K, Huh NH, Miyachi H. Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility. Bioorg Med Chem 2013; 21:2319-2332. [DOI: 10.1016/j.bmc.2013.02.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Revised: 02/02/2013] [Accepted: 02/04/2013] [Indexed: 11/16/2022]
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Tsukahara T, Haniu H, Matsuda Y. PTB-associated splicing factor (PSF) is a PPARγ-binding protein and growth regulator of colon cancer cells. PLoS One 2013; 8:e58749. [PMID: 23516550 PMCID: PMC3596311 DOI: 10.1371/journal.pone.0058749] [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: 12/04/2012] [Accepted: 02/05/2013] [Indexed: 11/19/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays an essential role in cell proliferation, apoptosis, and inflammation. It is over-expressed in many types of cancer, including colon, stomach, breast, and lung cancer, suggesting that regulation of PPARγ might affect cancer pathogenesis. Here, using a proteomic approach, we identify PTB-associated splicing factor (PSF) as a novel PPARγ-interacting protein and demonstrate that PSF is involved in several important regulatory steps of colon cancer cell proliferation. To investigate the relationship between PSF and PPARγ in colon cancer, we evaluated the effects of PSF expression in DLD-1 and HT-29 colon cancer cell lines, which express low and high levels of PPARγ, respectively PSF affected the ability of PPARγ to bind, and expression of PSF siRNA significantly suppressed the proliferation of colon cancer cells. Furthermore, PSF knockdown induced apoptosis via activation of caspase-3. Interestingly, DLD-1 cells were more susceptible to PSF knockdown-induced cell death than HT-29 cells. Our data suggest that PSF is an important regulator of cell death that plays critical roles in the survival and growth of colon cancer cells. The PSF-PPARγ axis may play a role in the control of colorectal carcinogenesis. Taken together, this study is the first to describe the effects of PSF on cell proliferation, tumor growth, and cell signaling associated with PPARγ.
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Affiliation(s)
- Tamotsu Tsukahara
- Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan.
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Kang S, Kim JB, Heo TH, Kim SJ. Cell cycle arrest in Batten disease lymphoblast cells. Gene 2013; 519:245-50. [PMID: 23458879 DOI: 10.1016/j.gene.2013.02.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 02/02/2013] [Accepted: 02/18/2013] [Indexed: 10/27/2022]
Abstract
Batten disease is an inherited neurodegenerative disorder caused by a CLN3 gene mutation. Batten disease is characterized by blindness, seizures, cognitive decline, and early death. Although apoptotic cell death is one of the pathological hallmarks of Batten disease, little is known about the regulatory mechanism of apoptosis in this disease. Since the CLN3 gene is suggested to be involved in the cell cycle in a yeast model, we investigated the cell cycle profile and its regulatory factors in lymphoblast cells from Batten disease patients. We found G1/G0 cell cycle arrest in Batten disease cells, with overexpression of p21, sphingosine, glucosylceramide, and sulfatide as possible cell cycle regulators.
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Affiliation(s)
- Sunyang Kang
- Department of Biotechnology, Hoseo University, 165 Baebang, Asan, Chungnam, Republic of Korea
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Carratù MR, Marasco C, Mangialardi G, Vacca A. Retinoids: novel immunomodulators and tumour-suppressive agents? Br J Pharmacol 2013; 167:483-92. [PMID: 22577845 DOI: 10.1111/j.1476-5381.2012.02031.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Retinoids play important roles in the transcriptional activity of normal, degenerative and tumour cells. Retinoid analogues may be promising therapeutic agents for the treatment of immune disorders as different as type I diabetes and systemic lupus erythematosus. In addition, the use of retinoids in cancer treatment has progressed significantly in the last two decades; thus, numerous retinoid compounds have been synthesized and tested. In this paper, the actual or potential use of retinoids as immunomodulators or tumour-suppressive agents is discussed.
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Affiliation(s)
- M R Carratù
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy
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Kimura O, Kondo Y, Shimosegawa T. PPAR Could Contribute to the Pathogenesis of Hepatocellular Carcinoma. PPAR Res 2012; 2012:574180. [PMID: 23316217 PMCID: PMC3533465 DOI: 10.1155/2012/574180] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 11/07/2012] [Accepted: 11/16/2012] [Indexed: 02/07/2023] Open
Abstract
Viral hepatitis with hepatitis C virus or hepatitis B virus and chronic liver disease such as alcoholic or nonalcoholic steatohepatitis are critical factors in the development of hepatocellular carcinoma (HCC). Furthermore, diabetes is known as an independent risk factor for HCC. Peroxisome proliferator-activated receptor (PPAR) is known to have an important role in fatty liver, and the mechanism of carcinogenesis has been clarified. PPAR controls ligand-dependent transcription, and three subtypes (α, δ, and γ) in humans are known. PPARs could contribute to the mechanisms of cell cycling, anti-inflammatory responses, and apoptosis. Therefore, to clarify the pathogenesis of HCC, we should examine PPAR signaling. In this paper, we have summarized the relevance of PPARs to the pathogenesis of HCC and cancer stem cells and possible therapeutic options through modifying PPAR signaling.
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Affiliation(s)
- Osamu Kimura
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
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Wu CW, Farrell GC, Yu J. Functional role of peroxisome-proliferator-activated receptor γ in hepatocellular carcinoma. J Gastroenterol Hepatol 2012; 27:1665-9. [PMID: 22742931 DOI: 10.1111/j.1440-1746.2012.07213.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Major risk factors of HCC include infection with hepatitis B or C viruses, alcohol and non-alcoholic fatty liver disease. HCC is difficult to diagnose at early stage, and has a very poor survival rate when diagnosed at a late stage. The majority of HCC-related deaths result from local invasion (to cause liver failure) or distant metastases. There is an urgent need to identify effective molecular targets for the treatment of the disease. As the target of an established class of therapeutic agent thiazolidinediones (TZDs), peroxisome-proliferator-activated receptor γ (PPARγ) has been widely studied for its role in the development of HCC. A substantial body of evidence based on in vitro and in vivo models indicates that the activation of PPARγ is able to inhibit HCC cell proliferation and tumor growth through inducing cell cycle arrest and apoptosis via the regulation of a panel of downstream effector molecules. PPARγ activation also induces an inhibitory effect on HCC metastasis. Meanwhile, there is new evidence suggesting that PPARγ inhibition could also be anti-tumorigenic. In the present review, we summarize the available information on the role of PPARγ in HCC development and spread, and discuss whether PPARγ activation by TZDs could play a role in the treatment of HCC, summarizing both in vitro and in vivo. Considering the available data, PPARγ seems to exert beneficial effects against HCC and may therefore represent as a therapeutic target.
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Affiliation(s)
- Chung-Wah Wu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong
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Avupati VR, Yejella RP, Akula A, Guntuku GS, Doddi BR, Vutla VR, Anagani SR, Adimulam LS, Vyricharla AK. Synthesis, characterization and biological evaluation of some novel 2,4-thiazolidinediones as potential cytotoxic, antimicrobial and antihyperglycemic agents. Bioorg Med Chem Lett 2012; 22:6442-50. [PMID: 22981328 DOI: 10.1016/j.bmcl.2012.08.052] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 07/13/2012] [Accepted: 08/14/2012] [Indexed: 10/28/2022]
Abstract
A series of some novel 2,4-thiazolidinediones (TZDs) (2a-x) have been synthesized and characterized by FTIR, (1)H NMR, (13)C NMR and LC mass spectral analysis. All the synthesized compounds were evaluated for their cytotoxicity, antimicrobial and in vivo antihyperglycemic activities. Among the tested compounds for cytotoxicity using Brine Shrimp Lethality assay, compound 2t ((Z)-5-(4-((E)-3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited significant inhibitory activity at ED(50) value 4.00±0.25 μg/mL and this level of activity was comparable to that of the reference drug podophyllotoxin with ED(50) value 3.61±0.17 μg/mL. Antimicrobial activity was screened using agar well diffusion assay method against selected Gram-positive, Gram-negative and fungal strains and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. From the results of antimicrobial activity compound 2s ((Z)-5-(4-((E)-3-(3,5-bis(benzyloxy)phenyl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) was found to be the most active against all the tested strains of microorganisms with MIC value 16 μg/mL. In vivo antihyperglycemic effect of twenty four TZDs (2a-x) at different doses 10, 30 and 50mg/kg b.w (oral) were assessed using percentage reduction of plasma glucose (PG) levels in streptozotocin-induced type II diabetic rat models. From the results, the novel compound 2x ((Z)-5-(4-((E)-3-(9H-fluoren-2-yl)-3-oxoprop-1-enyl)benzylidene)-1,3-thiazolidine-2,4-dione) exhibited considerably potent blood glucose lowering activity than that of the standard drug rosiglitazone and it could be a remarkable starting point to evaluate structure-activity relationships and to develop new lead molecules with potential cytotoxicity, antimicrobial and antihyperglycemic activities. In addition molecular docking studies were carried out against PPARγ molecular target using Molegro Virtual Docker v 4.0 to accomplish preliminary confirmation of the observed in vivo antihyperglycemic activity.
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Affiliation(s)
- Vasudeva Rao Avupati
- Pharmaceutical Chemistry Division, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India.
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Alegaon SG, Alagawadi KR. New thiazolidine-2,4-diones as antimicrobial and cytotoxic agent. Med Chem Res 2011. [DOI: 10.1007/s00044-011-9876-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Tanaka T, Hosokawa M, Yasui Y, Ishigamori R, Miyashita K. Cancer chemopreventive ability of conjugated linolenic acids. Int J Mol Sci 2011; 12:7495-509. [PMID: 22174613 PMCID: PMC3233419 DOI: 10.3390/ijms12117495] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 10/12/2011] [Accepted: 10/25/2011] [Indexed: 12/17/2022] Open
Abstract
Conjugated fatty acids (CFA) have received increased interest because of their beneficial effects on human health, including preventing cancer development. Conjugated linoleic acids (CLA) are such CFA, and have been reviewed extensively for their multiple biological activities. In contrast to other types of CFAs including CLA that are found at low concentrations (less than 1%) in natural products, conjugated linolenic acids (CLN) are the only CFAs that occur in higher quantities in natural products. Some plant seeds contain a considerably high concentration of CLN (30 to 70 wt% lipid). Our research group has screened CLN from different plant seed oils to determine their cancer chemopreventive ability. This review describes the physiological functions of CLN isomers that occur in certain plant seeds. CLN are able to induce apoptosis through decrease of Bcl-2 protein in certain human cancer cell lines, increase expression of peroxisome proliferator-activated receptor (PPAR)-γ, and up-regulate gene expression of p53. Findings in our preclinical animal studies have indicated that feeding with CLN resulted in inhibition of colorectal tumorigenesis through modulation of apoptosis and expression of PPARγ and p53. In this review, we summarize chemopreventive efficacy of CLN against cancer development, especially colorectal cancer.
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Affiliation(s)
- Takuji Tanaka
- The Tohkai Cytopathology Institute: Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285, Japan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-58-273-4399; Fax: +81-58-273-4392
| | - Masashi Hosokawa
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato-cho, Hakodate, Hokkaido 041-8611, Japan; E-Mail:
| | - Yumiko Yasui
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Midorimachi, Bunkyodai, Ebetsu, Hokkaido 069-8501, Japan; E-Mail:
| | - Rikako Ishigamori
- Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Research Institute, Chuo-ku, Tokyo 104-0045, Japan; E-Mail:
| | - Kazuo Miyashita
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato-cho, Hakodate, Hokkaido 041-8611, Japan; E-Mail:
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Pathophysiological Roles of PPARgamma in Gastrointestinal Epithelial Cells. PPAR Res 2011; 2008:148687. [PMID: 18615192 PMCID: PMC2443401 DOI: 10.1155/2008/148687] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2008] [Accepted: 05/19/2008] [Indexed: 12/11/2022] Open
Abstract
Although the highest levels of PPARγ expression in the body have been reported in the gastrointestinal epithelium, little is known about the physiological functions of that receptor in the gut. Moreover, there is considerable controversy concerning the effects of thiazolidinedione PPARγ agonists on the two major diseases of the gastrointestinal track: colorectal cancer and inflammatory bowel disease. We will undertake to review both historical and recently published data with a view toward summarizing what is presently known about the roles of PPARγ in both physiological and pathological processes in the gastrointestinal epithelium.
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CXCR4 in Cancer and Its Regulation by PPARgamma. PPAR Res 2011; 2008:769413. [PMID: 18779872 PMCID: PMC2528256 DOI: 10.1155/2008/769413] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2008] [Revised: 06/25/2008] [Accepted: 07/10/2008] [Indexed: 12/20/2022] Open
Abstract
Chemokines are peptide mediators involved in normal development,
hematopoietic and immune regulation, wound healing, and
inflammation. Among the chemokines is CXCL12, which binds
principally to its receptor CXCR4 and regulates leukocyte
precursor homing to bone marrow and other sites. This role of
CXCL12/CXCR4 is “commandeered” by cancer cells to facilitate the
spread of CXCR4-bearing tumor cells to tissues with high CXCL12
concentrations. High CXCR4 expression by cancer cells predisposes
to aggressive spread and metastasis and ultimately to poor patient
outcomes. As well as being useful as a marker for disease
progression, CXCR4 is a potential target for anticancer therapies.
It is possible to interfere directly with the CXCL12:CXCR4 axis
using peptide or small-molecular-weight antagonists. A further
opportunity is offered by promoting strategies that downregulate
CXCR4 pathways: CXCR4 expression in the tumor microenvironment is
modulated by factors such as hypoxia, nucleosides, and
eicosanoids. Another promising approach is through targeting PPAR
to suppress CXCR4 expression. Endogenous PPARγ such as 15-deoxy-Δ12,14-PGJ2 and synthetic agonists such as the
thiazolidinediones both cause downregulation of CXCR4 mRNA and
receptor. Adjuvant therapy using PPARγ agonists may, by
stimulating PPARγ-dependent downregulation of CXCR4 on cancer cells, slow the rate of metastasis and impact beneficially on
disease progression.
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Bloch O, Sughrue ME, Mills SA, Parsa AT. Signaling pathways in cranial chondrosarcoma: potential molecular targets for directed chemotherapy. J Clin Neurosci 2011; 18:881-5. [DOI: 10.1016/j.jocn.2010.09.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 09/08/2010] [Accepted: 09/10/2010] [Indexed: 12/31/2022]
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Campbell SE, Rudder B, Phillips RB, Whaley SG, Stimmel JB, Leesnitzer LM, Lightner J, Dessus-Babus S, Duffourc M, Stone WL, Menter DG, Newman RA, Yang P, Aggarwal BB, Krishnan K. γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer. Free Radic Biol Med 2011; 50:1344-54. [PMID: 21335085 DOI: 10.1016/j.freeradbiomed.2011.02.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 02/07/2011] [Accepted: 02/09/2011] [Indexed: 12/24/2022]
Abstract
Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.
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Affiliation(s)
- Sharon E Campbell
- Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
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Röhrl C, Kaindl U, Koneczny I, Hudec X, Baron DM, König JS, Marian B. Peroxisome-proliferator-activated receptors γ and β/δ mediate vascular endothelial growth factor production in colorectal tumor cells. J Cancer Res Clin Oncol 2011; 137:29-39. [PMID: 20221637 DOI: 10.1007/s00432-010-0856-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 02/19/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Peroxisome-proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids and their derivatives. PPAR subtypes PPARγ and PPARβ/δ are suspected to modulate cancer development in the colon, but their exact role is still discussed controversially. METHODS The present study investigated the impact of PPARγ and PPARβ/δ on vascular endothelial growth factor (VEGF) and cyclooxygenase 2 (COX-2) expressions induced by synthetic and physiological agonists in the colorectal tumor cell lines SW480 and HT29 using reporter gene assays, qRT-PCR and ELISA. RESULTS Activation of both PPARγ and PPARβ/δ induced expression of VEGF mRNA and protein in a PPAR-dependent way. The PPARγ agonists ciglitazone and PGJ(2) were the most effective inducers with up to ninefold and threefold increases in VEGF mRNA in SW480 and HT29 cultures, respectively. VEGF secretion was doubled in both cell lines. The PPARβ/δ agonists GW501516 and PGI(2) caused stimulations of only 1.5-fold in both cell lines. In addition, all PPAR agonists induced COX-2 mRNA and secretion of the COX-2 product PGE(2) in HT29 cells. However, this effect was not blocked by knock-down of PPAR expression nor was it essential for VEGF expression as shown by the lack of effect of the COX-2 inhibitor SC236. CONCLUSION In summary, our results identify both PPARγ and PPARβ/δ as an alternative COX-independent mechanism of VEGF induction in colorectal tumor cells.
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Affiliation(s)
- Clemens Röhrl
- Department of Medicine 1, Clinic for Internal Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
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PPARgamma Ligand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study. PPAR Res 2010; 2010. [PMID: 20814432 PMCID: PMC2929500 DOI: 10.1155/2010/257835] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 06/22/2010] [Accepted: 06/29/2010] [Indexed: 01/15/2023] Open
Abstract
Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARγ), such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARγ ligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF) have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day) group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8 ± 1.1 to 3.3 ± 2.3) after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARγ ligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.
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Bach-Ngohou K, Mahé MM, Aubert P, Abdo H, Boni S, Bourreille A, Denis MG, Lardeux B, Neunlist M, Masson D. Enteric glia modulate epithelial cell proliferation and differentiation through 15-deoxy-12,14-prostaglandin J2. J Physiol 2010; 588:2533-44. [PMID: 20478974 DOI: 10.1113/jphysiol.2010.188409] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The enteric nervous system (ENS) and its major component, enteric glial cells (EGCs), have recently been identified as a major regulator of intestinal epithelial barrier functions. Indeed, EGCs inhibit intestinal epithelial cell (IEC) proliferation and increase barrier resistance and IEC adhesion via the release of EGC-derived soluble factors. Interestingly, EGC regulation of intestinal epithelial barrier functions is reminiscent of previously reported peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent functional effects. In this context, the present study aimed at identifying whether EGC could synthesize and release the main PPARgamma ligand, 15-deoxy-(12,14)-prostaglandin J2 (15dPGJ2), and regulate IEC functions such as proliferation and differentiation via a PPARgamma dependent pathway. First, we demonstrated that the lipocalin but not the haematopoetic form for prostaglandin D synthase (PGDS), the enzyme responsible of 15dPGJ2 synthesis, was expressed in EGCs of the human submucosal plexus and of the subepithelium, as well as in rat primary culture of ENS and EGC lines. Next, 15dPGJ2 was identified in EGC supernatants of various EGC lines. 15dPGJ2 reproduced EGC inhibitory effects upon IEC proliferation, and inhibition of lipocalin PGDS expression by shRNA abrogated these effects. Furthermore, EGCs induced nuclear translocation of PPARgamma in IEC, and both EGC and 15dPGJ2 effects upon IEC proliferation were prevented by the PPARgamma antagonist GW9662. Finally, EGC induced differentiation-related gene expression in IEC through a PPARgamma-dependent pathway. Our results identified 15dPGJ2 as a novel glial-derived mediator involved in the control of IEC proliferation/differentiation through activation of PPARgamma. They also suggest that alterations of glial PGDS expression may modify intestinal epithelial barrier functions and be involved in the development of pathologies such as cancer or inflammatory bowel diseases.
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Affiliation(s)
- Kalyane Bach-Ngohou
- INSERM U913 and Institut des Maladies de l'Appareil Digestif, 1, place Alexis Ricordeau, 44093 Nantes Cedex 01, France.
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Voutsadakis IA. Peroxisome proliferator activated receptor-γ and the ubiquitin-proteasome system in colorectal cancer. World J Gastrointest Oncol 2010; 2:235-41. [PMID: 21160623 PMCID: PMC2998837 DOI: 10.4251/wjgo.v2.i5.235] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2009] [Revised: 11/30/2009] [Accepted: 12/07/2009] [Indexed: 02/05/2023] Open
Abstract
Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesis-related pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.
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Affiliation(s)
- Ioannis A Voutsadakis
- Ioannis A Voutsadakis, Department of Medical Oncology, University Hospital of Larissa, Larissa 41110, Greece
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