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Zhao B, Nepovimova E, Wu Q. The role of circadian rhythm regulator PERs in oxidative stress, immunity, and cancer development. Cell Commun Signal 2025; 23:30. [PMID: 39825442 PMCID: PMC11740368 DOI: 10.1186/s12964-025-02040-2] [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: 10/21/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
The complex interaction between circadian rhythms and physiological functions is essential for maintaining human health. At the heart of this interaction lies the PERIOD proteins (PERs), pivotal to the circadian clock, influencing the timing of physiological and behavioral processes and impacting oxidative stress, immune functionality, and tumorigenesis. PER1 orchestrates the cooperation of the enzyme GPX1, modulating mitochondrial dynamics in sync with daily rhythms and oxidative stress, thus regulating the mechanisms managing energy substrates. PERs in innate immune cells modulate the temporal patterns of NF-κB and TNF-α activities, as well as the response to LPS-induced toxic shock, initiating inflammatory responses that escalate into chronic inflammatory conditions. Crucially, PERs modulate cancer cell behaviors including proliferation, apoptosis, and migration by influencing the levels of cell cycle proteins and stimulating the expression of oncogenes c-Myc and MDM2. PER2/3, as antagonists in cancer stem cell biology, play important roles in differentiating cancer stem cells and in maintaining their stemness. Importantly, the expression of Pers serve as a significant factor for early cancer diagnosis and prognosis. This review delves into the link between circadian rhythm regulator PERs, disruptions in circadian rhythm, and oncogenesis. We examine the evidence that highlights how dysfunctions in PERs activities initiate cancer development, aid tumor growth, and modify cancer cell metabolism through pathways involved in oxidative stress and immune system. Comprehending these connections opens new pathways for the development of circadian rhythm-based therapeutic strategies, with the aims of boosting immune responses and enhancing cancer treatments.
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Affiliation(s)
- Baimei Zhao
- College of Life Science, Yangtze University, Jingzhou, 434025, China
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové , 500 03, Czech Republic
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, 434025, China.
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2
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Ali R, Zhen Y, Zanna X, Lin J, Zhang C, Ma J, Zhong Y, Husien HM, Saleh AA, Wang M. Impact of Circadian Clock PER2 Gene Overexpression on Rumen Epithelial Cell Dynamics and VFA Transport Protein Expression. Int J Mol Sci 2024; 25:12428. [PMID: 39596493 PMCID: PMC11594904 DOI: 10.3390/ijms252212428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
The circadian gene PER2 is recognized for its regulatory effects on cell proliferation and lipid metabolism across various non-ruminant cells. This study investigates the influence of PER2 gene overexpression on goat rumen epithelial cells using a constructed pcDNA3.1-PER2 plasmid, assessing its impact on circadian gene expression, cell proliferation, and mRNA levels of short-chain fatty acid (SCFA) transporters, alongside genes related to lipid metabolism, cell proliferation, and apoptosis. Rumen epithelial cells were obtained every four hours from healthy dairy goats (n = 3; aged 1.5 years; average weight 45.34 ± 4.28 kg), cultured for 48 h in vitro, and segregated into control (pcDNA3.1) and overexpressed (pcDNA3.1-PER2) groups, each with four biological replicates. The study examined the potential connection between circadian rhythms and nutrient assimilation in ruminant, including cell proliferation, apoptosis, cell cycle dynamics, and antioxidant activity and the expression of circadian-related genes, VFA transporter genes and regulatory factors. The introduction of the pcDNA3.1-PER2 plasmid drastically elevated PER2 expression levels by 3471.48-fold compared to controls (p < 0.01), confirming effective overexpression. PER2 overexpression resulted in a significant increase in apoptosis rates (p < 0.05) and a notable reduction in cell proliferation at 24 and 48 h post-transfection (p < 0.05), illustrating an inhibitory effect on rumen epithelial cell growth. PER2 elevation significantly boosted the expression of CCND1, WEE1, p21, and p16 (p < 0.05) while diminishing CDK4 expression (p < 0.05). While the general expression of intracellular inflammation genes remained stable, TNF-α expression notably increased. Antioxidant marker levels (SOD, MDA, GSH-Px, CAT, and T-AOC) exhibited no significant change, suggesting no oxidative damage due to PER2 overexpression. Furthermore, PER2 overexpression significantly downregulated AE2, NHE1, MCT1, and MCT4 mRNA expressions while upregulating PAT1 and VH+ ATPase. These results suggest that PER2 overexpression impairs cell proliferation, enhances apoptosis, and modulates VFA transporter-related factors in the rumen epithelium. This study implies that the PER2 gene may regulate VFA absorption through modulation of VFA transporters in rumen epithelial cells, necessitating further research into its specific regulatory mechanisms.
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Affiliation(s)
- Rahmat Ali
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Yongkang Zhen
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Xi Zanna
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Jiaqi Lin
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Chong Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Jianjun Ma
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Yuhong Zhong
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Hosameldeen Mohamed Husien
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
| | - Ahmad A. Saleh
- College of Animal Science & Technology, Yangzhou University, Yangzhou 225009, China;
| | - Mengzhi Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (R.A.); (H.M.H.)
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Dobrovinskaya O, Alamilla J, Olivas-Aguirre M. Impact of Modern Lifestyle on Circadian Health and Its Contribution to Adipogenesis and Cancer Risk. Cancers (Basel) 2024; 16:3706. [PMID: 39518143 PMCID: PMC11545514 DOI: 10.3390/cancers16213706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Recent research underscores a crucial connection between circadian rhythm disruption and cancer promotion, highlighting an urgent need for attention. OBJECTIVES Explore the molecular mechanisms by which modern lifestyle factors-such as artificial light exposure, shift work, and dietary patterns-affect cortisol/melatonin regulation and cancer risk. METHODS Employing a narrative review approach, we synthesized findings from Scopus, Google Scholar, and PubMed to analyze lifestyle impacts on circadian health, focusing on cortisol and melatonin chronobiology as molecular markers. We included studies that documented quantitative changes in these markers due to modern lifestyle habits, excluding those lacking quantitative data or presenting inconclusive results. Subsequent sections focused solely on articles that quantified the effects of circadian disruption on adipogenesis and tumor microenvironment modifications. RESULTS This review shows how modern habits lead to molecular changes in cortisol and melatonin, creating adipose microenvironments that support cancer development. These disruptions facilitate immune evasion, chemotherapy resistance, and tumor growth, highlighting the critical roles of cortisol dysregulation and melatonin imbalance. CONCLUSIONS Through the presented findings, we establish a causal link between circadian rhythm dysregulation and the promotion of certain cancer types. By elucidating this relationship, the study emphasizes the importance of addressing lifestyle factors that contribute to circadian misalignment, suggesting that targeted interventions could play a crucial role in mitigating cancer risk and improving overall health outcomes.
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Affiliation(s)
- Oxana Dobrovinskaya
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima 28040, Mexico;
| | - Javier Alamilla
- Consejo Nacional de Humanidades, Ciencia y Tecnología (CONAHCYT), Programa de Investigadores e Investigadoras por México, México City 03940, Mexico;
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima 28040, Mexico
| | - Miguel Olivas-Aguirre
- Consejo Nacional de Humanidades, Ciencia y Tecnología (CONAHCYT), Programa de Investigadores e Investigadoras por México, México City 03940, Mexico;
- Laboratory of Cancer Pathophysiology, University Center for Biomedical Research, University of Colima, Colima 28040, Mexico
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El-Hennamy RE, Elmasry HA. Alterations in Per2, Bcl2 gene expression, and oxidative status in aged rats liver after light pulse at night. Sleep Biol Rhythms 2024; 22:181-190. [PMID: 38524161 PMCID: PMC10959914 DOI: 10.1007/s41105-023-00495-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 10/06/2023] [Indexed: 03/26/2024]
Abstract
The aging process is characterized by circadian rhythm disruption, in physiology and behavior, which could result from weak entrainment. Light is the most potent cue that entrains the central circadian clock, which in turn synchronizes peripheral clocks in animal tissues. Period 2 (Per2) is one of the clock genes that respond to light. Moreover, oxidative stress could entrain the clock. Therefore, the present work aimed to investigate the role of light when applied late at night on the Per2, B cell lymphoma 2 (Bcl2) gene expression, and oxidative status in aged rats. Aged rats were divided into a control group and a group exposed to a 30-min light pulse applied daily during the subjective night at 5 am (ZT 22) for 4 weeks. Per2 and Bcl2 gene expression were quantified in liver tissue. To evaluate oxidative status, Glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were estimated. The light pulse reduced the expression levels of Per2 and Bcl2 mRNA. Although it diminished the levels of malondialdehyde (MDA), nitric oxide (NO) levels were elevated and the glutathione (GSH) levels were declined. In conclusion, the light pulse late at night abolished Per2 mRNA circadian rhythm and reduced its expression in the liver of the aged rat. Similarly, it diminished the anti-apoptotic gene expression, Bcl2. Moreover, it might attenuate oxidative stress through the reduction in MDA levels.
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Affiliation(s)
- Rehab E. El-Hennamy
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Heba A. Elmasry
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
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Tsilingiris D, Vallianou NG, Spyrou N, Kounatidis D, Christodoulatos GS, Karampela I, Dalamaga M. Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges. Curr Obes Rep 2024; 13:1-34. [PMID: 38159164 PMCID: PMC10933194 DOI: 10.1007/s13679-023-00542-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, 68100, Alexandroupolis, Greece
| | - Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Nikolaos Spyrou
- Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, 1190 One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Dimitris Kounatidis
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | | | - Irene Karampela
- 2nd Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini Str, 12462, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias str, 11527, Athens, Greece.
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Astone M, Oberkersch RE, Tosi G, Biscontin A, Santoro MM. The circadian protein BMAL1 supports endothelial cell cycle during angiogenesis. Cardiovasc Res 2023; 119:1952-1968. [PMID: 37052172 DOI: 10.1093/cvr/cvad057] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 02/23/2023] [Accepted: 03/11/2023] [Indexed: 04/14/2023] Open
Abstract
AIMS The circadian clock is an internal biological timer that co-ordinates physiology and gene expression with the 24-h solar day. Circadian clock perturbations have been associated to vascular dysfunctions in mammals, and a function of the circadian clock in angiogenesis has been suggested. However, the functional role of the circadian clock in endothelial cells (ECs) and in the regulation of angiogenesis is widely unexplored. METHODS AND RESULTS Here, we used both in vivo and in vitro approaches to demonstrate that ECs possess an endogenous molecular clock and show robust circadian oscillations of core clock genes. By impairing the EC-specific function of the circadian clock transcriptional activator basic helix-loop-helix ARNT like 1 (BMAL1) in vivo, we detect angiogenesis defects in mouse neonatal vascular tissues, as well as in adult tumour angiogenic settings. We then investigate the function of circadian clock machinery in cultured EC and show evidence that BMAL and circadian locomotor output cycles protein kaput knock-down impair EC cell cycle progression. By using an RNA- and chromatin immunoprecipitation sequencing genome-wide approaches, we identified that BMAL1 binds the promoters of CCNA1 and CDK1 genes and controls their expression in ECs. CONCLUSION(S) Our findings show that EC display a robust circadian clock and that BMAL1 regulates EC physiology in both developmental and pathological contexts. Genetic alteration of BMAL1 can affect angiogenesis in vivo and in vitro settings.
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Affiliation(s)
- Matteo Astone
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
| | - Roxana E Oberkersch
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
| | - Giovanni Tosi
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
| | - Alberto Biscontin
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
| | - Massimo M Santoro
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
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Chi H, Yang J, Peng G, Zhang J, Song G, Xie X, Xia Z, Liu J, Tian G. Circadian rhythm-related genes index: A predictor for HNSCC prognosis, immunotherapy efficacy, and chemosensitivity. Front Immunol 2023; 14:1091218. [PMID: 36969232 PMCID: PMC10036372 DOI: 10.3389/fimmu.2023.1091218] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is the most common head and neck cancer and is highly aggressive and heterogeneous, leading to variable prognosis and immunotherapy outcomes. Circadian rhythm alterations in tumourigenesis are of equal importance to genetic factors and several biologic clock genes are considered to be prognostic biomarkers for various cancers. The aim of this study was to establish reliable markers based on biologic clock genes, thus providing a new perspective for assessing immunotherapy response and prognosis in patients with HNSCC. METHODS We used 502 HNSCC samples and 44 normal samples from the TCGA-HNSCC dataset as the training set. 97 samples from GSE41613 were used as an external validation set. Prognostic characteristics of circadian rhythm-related genes (CRRGs) were established by Lasso, random forest and stepwise multifactorial Cox. Multivariate analysis revealed that CRRGs characteristics were independent predictors of HNSCC, with patients in the high-risk group having a worse prognosis than those in the low-risk group. The relevance of CRRGs to the immune microenvironment and immunotherapy was assessed by an integrated algorithm. RESULTS 6-CRRGs were considered to be strongly associated with HNSCC prognosis and a good predictor of HNSCC. The riskscore established by the 6-CRRG was found to be an independent prognostic factor for HNSCC in multifactorial analysis, with patients in the low-risk group having a higher overall survival (OS) than the high-risk group. Nomogram prediction maps constructed from clinical characteristics and riskscore had good prognostic power. Patients in the low-risk group had higher levels of immune infiltration and immune checkpoint expression and were more likely to benefit from immunotherapy. CONCLUSION 6-CRRGs play a key predictive role for the prognosis of HNSCC patients and can guide physicians in selecting potential responders to prioritise immunotherapy, which could facilitate further research in precision immuno-oncology.
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Affiliation(s)
- Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Jinyan Yang
- School of Stomatology, Southwest Medical University, Luzhou, China
| | - Gaoge Peng
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Jinhao Zhang
- School of Stomatology, Southwest Medical University, Luzhou, China
| | - Guobin Song
- School of Stomatology, Southwest Medical University, Luzhou, China
| | - Xixi Xie
- School of Stomatology, Southwest Medical University, Luzhou, China
| | - Zhijia Xia
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gang Tian
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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8
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Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy. Int J Mol Sci 2022; 23:ijms232214181. [PMID: 36430659 PMCID: PMC9698777 DOI: 10.3390/ijms232214181] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Circadian rhythms, including sleep/wake cycles as well as hormonal, immune, metabolic, and cell proliferation rhythms, are fundamental biological processes driven by a cellular time-keeping system called the circadian clock. Disruptions in these rhythms due to genetic alterations or irregular lifestyles cause fundamental changes in physiology, from metabolism to cellular proliferation and differentiation, resulting in pathological consequences including cancer. Cancer cells are not uniform and static but exist as different subtypes with phenotypic and functional differences in the tumor microenvironment. At the top of the heterogeneous tumor cell hierarchy, cancer stem cells (CSCs), a self-renewing and multi-potent cancer cell type, are most responsible for tumor recurrence and metastasis, chemoresistance, and mortality. Phenotypically, CSCs are associated with the epithelial-mesenchymal transition (EMT), which confers cancer cells with increased motility and invasion ability that is characteristic of malignant and drug-resistant stem cells. Recently, emerging studies of different cancer types, such as glioblastoma, leukemia, prostate cancer, and breast cancer, suggest that the circadian clock plays an important role in the maintenance of CSC/EMT characteristics. In this review, we describe recent discoveries regarding how tumor intrinsic and extrinsic circadian clock-regulating factors affect CSC evolution, highlighting the possibility of developing novel chronotherapeutic strategies that could be used against CSCs to fight cancer.
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Olejárová S, Moravčík R, Herichová I. 2.4 GHz Electromagnetic Field Influences the Response of the Circadian Oscillator in the Colorectal Cancer Cell Line DLD1 to miR-34a-Mediated Regulation. Int J Mol Sci 2022; 23:13210. [PMID: 36361993 PMCID: PMC9656412 DOI: 10.3390/ijms232113210] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 10/15/2023] Open
Abstract
Radiofrequency electromagnetic fields (RF-EMF) exert pleiotropic effects on biological processes including circadian rhythms. miR-34a is a small non-coding RNA whose expression is modulated by RF-EMF and has the capacity to regulate clock gene expression. However, interference between RF-EMF and miR-34a-mediated regulation of the circadian oscillator has not yet been elucidated. Therefore, the present study was designed to reveal if 24 h exposure to 2.4 GHz RF-EMF influences miR-34a-induced changes in clock gene expression, migration and proliferation in colorectal cancer cell line DLD1. The effect of up- or downregulation of miR-34a on DLD1 cells was evaluated using real-time PCR, the scratch assay test and the MTS test. Administration of miR-34a decreased the expression of per2, bmal1, sirtuin1 and survivin and inhibited proliferation and migration of DLD1 cells. When miR-34a-transfected DLD1 cells were exposed to 2.4 GHz RF-EMF, an increase in cry1 mRNA expression was observed. The inhibitory effect of miR-34a on per2 and survivin was weakened and abolished, respectively. The effect of miR-34a on proliferation and migration was eliminated by RF-EMF exposure. In conclusion, RF-EMF strongly influenced regulation mediated by the tumour suppressor miR-34a on the peripheral circadian oscillator in DLD1 cells.
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Affiliation(s)
| | | | - Iveta Herichová
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University Bratislava, 842 15 Bratislava, Slovakia
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10
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Sanford ABA, da Cunha LS, Machado CB, de Pinho Pessoa FMC, Silva ANDS, Ribeiro RM, Moreira FC, de Moraes Filho MO, de Moraes MEA, de Souza LEB, Khayat AS, Moreira-Nunes CA. Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers. Int J Mol Sci 2022; 23:ijms23158212. [PMID: 35897788 PMCID: PMC9332415 DOI: 10.3390/ijms23158212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/08/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC’s interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.
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Affiliation(s)
- Ana Beatriz Aguiar Sanford
- Unichristus University Center, Faculty of Biomedicine, Fortaleza 60430-275, CE, Brazil; (A.B.A.S.); (L.S.d.C.)
| | - Leidivan Sousa da Cunha
- Unichristus University Center, Faculty of Biomedicine, Fortaleza 60430-275, CE, Brazil; (A.B.A.S.); (L.S.d.C.)
| | - Caio Bezerra Machado
- Pharmacogenetics Laboratory, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil; (C.B.M.); (F.M.C.d.P.P.); (M.O.d.M.F.); (M.E.A.d.M.)
| | - Flávia Melo Cunha de Pinho Pessoa
- Pharmacogenetics Laboratory, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil; (C.B.M.); (F.M.C.d.P.P.); (M.O.d.M.F.); (M.E.A.d.M.)
| | - Abigail Nayara dos Santos Silva
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém 66073-005, PA, Brazil; (A.N.d.S.S.); (F.C.M.); (A.S.K.)
| | | | - Fabiano Cordeiro Moreira
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém 66073-005, PA, Brazil; (A.N.d.S.S.); (F.C.M.); (A.S.K.)
| | - Manoel Odorico de Moraes Filho
- Pharmacogenetics Laboratory, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil; (C.B.M.); (F.M.C.d.P.P.); (M.O.d.M.F.); (M.E.A.d.M.)
| | - Maria Elisabete Amaral de Moraes
- Pharmacogenetics Laboratory, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil; (C.B.M.); (F.M.C.d.P.P.); (M.O.d.M.F.); (M.E.A.d.M.)
| | - Lucas Eduardo Botelho de Souza
- Center for Cell-Based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, São Paulo 14051-140, SP, Brazil;
| | - André Salim Khayat
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém 66073-005, PA, Brazil; (A.N.d.S.S.); (F.C.M.); (A.S.K.)
| | - Caroline Aquino Moreira-Nunes
- Unichristus University Center, Faculty of Biomedicine, Fortaleza 60430-275, CE, Brazil; (A.B.A.S.); (L.S.d.C.)
- Pharmacogenetics Laboratory, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil; (C.B.M.); (F.M.C.d.P.P.); (M.O.d.M.F.); (M.E.A.d.M.)
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém 66073-005, PA, Brazil; (A.N.d.S.S.); (F.C.M.); (A.S.K.)
- Northeast Biotechnology Network (RENORBIO), Itaperi Campus, Ceará State University, Fortaleza 60740-903, CE, Brazil
- Correspondence:
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11
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Malik S, Stokes Iii J, Manne U, Singh R, Mishra MK. Understanding the significance of biological clock and its impact on cancer incidence. Cancer Lett 2022; 527:80-94. [PMID: 34906624 PMCID: PMC8816870 DOI: 10.1016/j.canlet.2021.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022]
Abstract
The circadian clock is an essential timekeeper that controls, for humans, the daily rhythm of biochemical, physiological, and behavioral functions. Irregular performance or disruption in circadian rhythms results in various diseases, including cancer. As a factor in cancer development, perturbations in circadian rhythms can affect circadian homeostasis in energy balance, lead to alterations in the cell cycle, and cause dysregulation of chromatin remodeling. However, knowledge gaps remain in our understanding of the relationship between the circadian clock and cancer. Therefore, a mechanistic understanding by which circadian disruption enhances cancer risk is needed. This review article outlines the importance of the circadian clock in tumorigenesis and summarizes underlying mechanisms in the clock and its carcinogenic mechanisms, highlighting advances in chronotherapy for cancer treatment.
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Affiliation(s)
- Shalie Malik
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA; Department of Zoology and Dr. Giri Lal Gupta Institute of Public Health and Public Affairs, University of Lucknow, Lucknow, UP, India
| | - James Stokes Iii
- Department of Biological and Environmental Sciences, Auburn University, Montgomery, AL, USA
| | - Upender Manne
- Departments of Pathology, Surgery and Epidemiology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Manoj K Mishra
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA.
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12
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Jing Y, Chen Y, Wang S, Ouyang J, Hu L, Yang Q, Wang M, Zhang B, Loor JJ. Circadian Gene PER2 Silencing Downregulates PPARG and SREBF1 and Suppresses Lipid Synthesis in Bovine Mammary Epithelial Cells. BIOLOGY 2021; 10:biology10121226. [PMID: 34943141 PMCID: PMC8698707 DOI: 10.3390/biology10121226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 01/01/2023]
Abstract
Simple Summary The present study was constructed to determine the effects of the core circadian clock gene, Period 2 (PER2), on lipid synthesis in bovine mammary epithelial cells (BMECs). Data revealed that PER2-regulated genes were involved in fatty acid de novo synthesis, desaturation, TAG accumulation, and lipid droplet secretion in primary BMECs, partly by inhibiting PPARG and SREBF1. Our overall data suggests that PER2 in bovine mammary cells plays a role in regulating milk fat synthesis directly, or via the activation of the transcription regulators PPARG and SREBF1. This study provides molecular evidence underscoring a link between the circadian clock and lipid metabolism in bovines. Abstract PER2, a circadian clock gene, is associated with mammary gland development and lipid synthesis in rodents, partly via regulating peroxisome proliferator-activated receptor gamma (PPARG). Whether such a type of molecular link existed in bovines was unclear. We hypothesized that PER2 was associated with lipid metabolism and regulated cell cycles and apoptosis in bovine mammary epithelial cells (BMECs). To test this hypothesis, BMECs isolated from three mid-lactation (average 110 d postpartum) cows were used. The transient transfection of small interfering RNA (siRNA) was used to inhibit PER2 transcription in primary BMECs. The silencing of PER2 led to lower concentrations of cellular lipid droplets and triacylglycerol along with the downregulation of lipogenic-related genes such as ACACA, FASN, LPIN1, and SCD, suggesting an overall inhibition of lipogenesis and desaturation. The downregulation of PPARG and SREBF1 in response to PER2 silencing underscored the importance of circadian clock signaling and the transcriptional regulation of lipogenesis. Although the proliferation of BMECs was not influenced by PER2 silencing, the number of cells in the G2/GM phase was upregulated. PER2 silencing did not affect cell apoptosis. Overall, the data provided evidence that PER2 participated in the coordination of mammary lipid metabolism and was potentially a component of the control of lipid droplets and TAG synthesis in ruminant mammary cells. The present data suggested that such an effect could occur through direct effects on transcriptional regulators.
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Affiliation(s)
- Yujia Jing
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi 832000, China; (Y.J.); (Q.Y.)
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
| | - Yifei Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
| | - Shan Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
| | - Jialiang Ouyang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
| | - Liangyu Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
| | - Qingyong Yang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi 832000, China; (Y.J.); (Q.Y.)
| | - Mengzhi Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.C.); (S.W.); (J.O.); (L.H.)
- Correspondence: (M.W.); (B.Z.); (J.J.L.)
| | - Bin Zhang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi 832000, China; (Y.J.); (Q.Y.)
- Correspondence: (M.W.); (B.Z.); (J.J.L.)
| | - Juan J. Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA
- Correspondence: (M.W.); (B.Z.); (J.J.L.)
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13
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PER2: a potential molecular marker for hematological malignancies. Mol Biol Rep 2021; 48:7587-7595. [PMID: 34642831 DOI: 10.1007/s11033-021-06751-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/16/2021] [Indexed: 11/27/2022]
Abstract
Circadian rhythm is a periodic change of organism according to the law of external environment, which is manifested in metabolism, cell proliferation, physiology and behavior. In recent years, the role of circadian genes in the occurrence and progression of hematological malignancies have been continuously demonstrated. PER2 is the core component of the circadian rhythm playing an important role in regulating the circadian rhythm of the biological clock. This review summarizes the research progress of PER2 in hematological malignancies, especially leukemia, in order to better understand its role in hematological malignancies, and provide new ideas for clinical diagnosis and treatment.
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14
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Lee Y. Roles of circadian clocks in cancer pathogenesis and treatment. Exp Mol Med 2021; 53:1529-1538. [PMID: 34615982 PMCID: PMC8568965 DOI: 10.1038/s12276-021-00681-0] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/29/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Circadian clocks are ubiquitous timing mechanisms that generate approximately 24-h rhythms in cellular and bodily functions across nearly all living species. These internal clock systems enable living organisms to anticipate and respond to daily changes in their environment in a timely manner, optimizing temporal physiology and behaviors. Dysregulation of circadian rhythms by genetic and environmental risk factors increases susceptibility to multiple diseases, particularly cancers. A growing number of studies have revealed dynamic crosstalk between circadian clocks and cancer pathways, providing mechanistic insights into the therapeutic utility of circadian rhythms in cancer treatment. This review will discuss the roles of circadian rhythms in cancer pathogenesis, highlighting the recent advances in chronotherapeutic approaches for improved cancer treatment.
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Affiliation(s)
- Yool Lee
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, 99202, USA.
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15
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Wagner PM, Prucca CG, Caputto BL, Guido ME. Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy. Int J Mol Sci 2021; 22:8289. [PMID: 34361055 PMCID: PMC8348990 DOI: 10.3390/ijms22158289] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.
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Affiliation(s)
- Paula M. Wagner
- CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; (P.M.W.); (C.G.P.); (B.L.C.)
- Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
| | - César G. Prucca
- CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; (P.M.W.); (C.G.P.); (B.L.C.)
- Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
| | - Beatriz L. Caputto
- CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; (P.M.W.); (C.G.P.); (B.L.C.)
- Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
| | - Mario E. Guido
- CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; (P.M.W.); (C.G.P.); (B.L.C.)
- Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
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16
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Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy. Int J Mol Sci 2021; 22:8289. [PMID: 34361055 PMCID: PMC8348990 DOI: 10.3390/ijms22158289;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.
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17
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Exploring the link between chronobiology and drug delivery: effects on cancer therapy. J Mol Med (Berl) 2021; 99:1349-1371. [PMID: 34213595 DOI: 10.1007/s00109-021-02106-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 02/01/2023]
Abstract
Circadian clock is an impressive timing system responsible for the control of several metabolic, physiological and behavioural processes. Nowadays, the connection between the circadian clock and cancer occurrence and development is consensual. Therefore, the inclusion of circadian timing into cancer therapy may potentially offer a more effective and less toxic approach. This way, chronotherapy has been shown to improve cancer treatment efficacy. Despite this relevant finding, its clinical application is poorly exploited. The conception of novel anticancer drug delivery systems and the combination of chronobiology with nanotechnology may provide a powerful tool to optimize cancer therapy, instigating the incorporation of the circadian timing into clinical practice towards a more personalized drug delivery. This review focuses on the recent advances in the field of cancer chronobiology, on the link between cancer and the disruption of circadian rhythms and on the promising targeted drug nanodelivery approaches aiming the clinical application of cancer chronotherapy.
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18
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Abstract
Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA-repair enzymes. While CRYs lack DNA-repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SKP1 cullin 1-F-box (SCF)FBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady-state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3 Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target-gene expression, suggesting that this may be a primary mechanism by which they influence cell growth.
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19
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Cash E, Sephton S, Woolley C, Elbehi AM, R I A, Ekine-Afolabi B, Kok VC. The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics. J Exp Clin Cancer Res 2021; 40:119. [PMID: 33794967 PMCID: PMC8017624 DOI: 10.1186/s13046-021-01919-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.
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Affiliation(s)
- Elizabeth Cash
- Department of Otolaryngology and Communicative Disorders, University of Louisville School of Medicine, James Graham Brown Cancer Center, 529 S Jackson Street, Louisville, KY, 40202, USA.
| | - Sandra Sephton
- Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, USA
| | - Cassandra Woolley
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Attia M Elbehi
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Anu R I
- Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Kerala, India
| | - Bene Ekine-Afolabi
- ZEAB Therapeutic Ltd, London, UK
- Department of Health, Sport & Bioscience, University of East London, Stratford, UK
| | - Victor C Kok
- Department of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University Taiwan, Taichung, Taiwan
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20
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Astone M, Santoro MM. Time to fight: targeting the circadian clock molecular machinery in cancer therapy. Drug Discov Today 2021; 26:1164-1184. [PMID: 33549826 DOI: 10.1016/j.drudis.2021.01.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/23/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023]
Abstract
The circadian clock regulates a wide range of molecular pathways and biological processes. The expression of clock genes is often altered in cancer, fostering tumor initiation and progression. Inhibition and activation of core circadian clock genes, as well as treatments that restore circadian rhythmicity, have been successful in counteracting tumor growth in different experimental models. Here, we provide an up-to-date overview of studies that show the therapeutic effects of targeting the clock molecular machinery in cancer, both genetically and pharmacologically. We also highlight future areas for progress that offer a promising path towards innovative anticancer strategies. Substantial limitations in the current understanding of the complex interplay between the circadian clock and cancer in vivo need to be addressed in order to allow clock-targeting therapies in cancer.
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Affiliation(s)
- Matteo Astone
- Department of Biology, University of Padova, I-35131, Italy
| | - Massimo M Santoro
- Department of Biology, University of Padova, I-35131, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
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21
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Wagner PM, Prucca CG, Velazquez FN, Sosa Alderete LG, Caputto BL, Guido ME. Temporal regulation of tumor growth in nocturnal mammals: In vivo studies and chemotherapeutical potential. FASEB J 2021; 35:e21231. [PMID: 33428275 DOI: 10.1096/fj.202001753r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/28/2020] [Accepted: 11/12/2020] [Indexed: 11/11/2022]
Abstract
Tumors of the nervous system including glioblastoma multiforme (GBM) are the most frequent and aggressive form of brain tumors; however, little is known about the impact of the circadian timing system on the formation, growth, and treatment of these tumors. We investigated day/night differences in tumor growth after injection of A530 glioma cells isolated from malignant peripheral nerve sheath tumor (MPNSTs) of NPcis (Trp53+/- ; Nf1+/- ) mice. Synchronized A530 cell cultures expressing typical glial markers were injected at the beginning of the day or night into the sciatic nerve zone of C57BL/6 mice subject to a 12:12 hours light/dark (LD) cycle or after being released to constant darkness (DD). Tumors generated in animals injected early at night in the LD cycle or in DD showed higher growth rates than in animals injected diurnally. No differences were found when animals were injected at the same time with cultures synchronized 12 hours apart. Similar experiments performed with B16 melanoma cells showed higher tumor growth rates in animals injected at the beginning of the night compared to those injected in the daytime. A higher tumor growth rate than that in controls was observed when mice were injected with knocked-down clock gene Bmal1 cells. Finally, when we compared day/night administration of different doses of the proteasome inhibitor Bortezomib (0.5-1.5 mg/kg) in tumor-bearing animals, we found that low-dose chemotherapy displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.
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Affiliation(s)
- Paula M Wagner
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC)-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
- Departamento de Química Biológica "Ranwel Caputto", Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - César G Prucca
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC)-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
- Departamento de Química Biológica "Ranwel Caputto", Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Fabiola N Velazquez
- Stony Brook Cancer Center and the Department of Medicine,, Stony Brook University, Stony Brook, USA
| | - Lucas G Sosa Alderete
- Instituto de Biotecnología Ambiental y Salud (INBIAS, UNRC-CONICET). Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, Córdoba, Argentina
| | - Beatriz L Caputto
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC)-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
- Departamento de Química Biológica "Ranwel Caputto", Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Mario E Guido
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC)-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
- Departamento de Química Biológica "Ranwel Caputto", Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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22
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Wang Z, Li F, Wei M, Zhang S, Wang T. Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer. Cancer Manag Res 2020; 12:11897-11908. [PMID: 33244267 PMCID: PMC7683831 DOI: 10.2147/cmar.s278903] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background The mortality rate of ovarian cancer is the highest among gynecological tumors. The two factors leading to high mortality of ovarian cancer are late clinical stage and chemotherapy resistance. It is very important to reverse or intervene chemotherapy resistance. Abnormal circadian rhythm is related to the occurrence of tumor, and circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity. Methods This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues. Results Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1 while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment. Conclusion This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.
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Affiliation(s)
- Zhaoxia Wang
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China
| | - Fengyan Li
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China
| | - Meiyan Wei
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China
| | - Sanyuan Zhang
- Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China
| | - Tong Wang
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China
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Period Family of Clock Genes as Novel Predictors of Survival in Human Cancer: A Systematic Review and Meta-Analysis. DISEASE MARKERS 2020; 2020:6486238. [PMID: 32849922 PMCID: PMC7436287 DOI: 10.1155/2020/6486238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/03/2020] [Accepted: 05/05/2020] [Indexed: 01/15/2023]
Abstract
Background Period genes are important core clock genes, including PER1, PER2, and PER3. A number of studies have demonstrated that the abnormal expression of the PER gene family of clock genes is associated with the survival and prognosis of patients with cancer; however, the sample sizes included in the majority of these studies were small, and the reported results were inconsistent. This study was the first to collect the relevant publications to systematically evaluate the value of the expression of the PER gene family in the prediction of survival and prognosis of human tumors. Methods The PubMed, Cochrane Library, Embase, and Web of Science databases were searched systematically, and a meta-analysis was performed. Results A total of 12 eligible publications met the inclusion criteria for the meta-analysis, including 1,369 patients and 9 different types of cancer. The pooled hazard ratio for overall survival indicated that the overall survival of patients in the high PER1, PER2, and PER3 protein expression group was significantly higher than that in the low-expression group, respectively. The sensitivity analysis revealed that the result was stable and reliable. The association between PER1 and PER3 mRNA expression levels and cancer prognosis was not meta-analyzed as the number of experimental studies was <3. There was no significant association between the expression of PER2 mRNA and the overall survival of patients with cancer. Conclusion PER1, PER2, and PER3 protein expression levels can be used as novel potential biomarkers for predicting cancer prognosis.
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Yang C, Wu J, Liu X, Wang Y, Liu B, Chen X, Wu X, Yan D, Han L, Liu S, Shan L, Shang Y. Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis. Cancer Res 2020; 80:4114-4128. [PMID: 32651256 DOI: 10.1158/0008-5472.can-20-0493] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/26/2020] [Accepted: 07/07/2020] [Indexed: 11/16/2022]
Abstract
Copy number gain in chromosome 8q21 is frequently detected in breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. ZNF704 acted as a transcriptional repressor and interacted with the transcriptional corepressor SIN3A complex. Genome-wide interrogation of transcriptional targets revealed that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of the circadian clock. Overexpression of ZNF704 prolonged the period and dampened the amplitude of the circadian clock. ZNF704 promoted the proliferation and invasion of breast cancer cells in vitro and accelerated the growth and metastasis of breast cancer in vivo. Consistently, the level of ZNF704 expression inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlated with advanced histologic grades, lymph node positivity, and poor prognosis of patients with breast cancer, especially those with HER2+ and basal-like subtypes. These results indicate that ZNF704 is an important regulator of the circadian clock and a potential driver for breast carcinogenesis. SIGNIFICANCE: This study indicates that ZNF704 could be a potential oncogenic factor, disrupting circadian rhythm of breast cancer cells and contributing to breast carcinogenesis.
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Affiliation(s)
- Chao Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jiajing Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xinhua Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Yue Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Beibei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xing Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaodi Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Dong Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lulu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shumeng Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lin Shan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yongfeng Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. .,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China.,Laboratory of Cancer Epigenetics, Chinese Academy of Medical Sciences Beijing, China
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Zhang J, Lv H, Ji M, Wang Z, Wu W. Low circadian clock genes expression in cancers: A meta-analysis of its association with clinicopathological features and prognosis. PLoS One 2020; 15:e0233508. [PMID: 32437452 PMCID: PMC7241715 DOI: 10.1371/journal.pone.0233508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/06/2020] [Indexed: 02/06/2023] Open
Abstract
Background Per1, Per2, Per3, Cry1, Cry2, Bmal1, Npas2 and CLOCK genes are the eight core circadian clock genes. Low expression of these circadian clock genes plays an important role in the progression of cancers. However, its clinicopathological and prognostic value in patients with cancers remains controversial and inconclusive. We performed a meta-analysis of studies assessing the clinicopathological and prognostic significance of low expression of these genes in cancers. Methods Relevant studies were searched from the Cochrane Central Register of Controlled Trials, Embase, EBSCO, Ovid, PubMed, Science Direct, Wiley Online Library database, CNKI and Wan Fang database. The meta-analysis was performed by using STATA version 12 software. A random-effect model was employed to evaluate all pooled hazard ratios (HRs) and odd ratios (ORs). Results A total of 36 studies comprising 7476 cases met the inclusion criteria. Meta-analysis suggested that low expression of Per1 was associated with poor differentiation (Per1: OR=2.30, 95%CI: 1.36∼3.87, P=0.002) and deeper invasion depth (Per1: OR=2.12, 95%CI: 1.62∼2.77, Ρ<0.001); low Per2 expression was correlated with poor differentiation (Per2: OR=2.41, 95%CI: 1.53∼3.79, Ρ<0.001), worse TNM stage (Per2:OR=3.47, 95%CI: 1.88∼6.42, P<0.001) and further metastasis (Per2:OR=2.35, 95%CI: 1.35∼4.11, Ρ=0.003). Furthermore, the results revealed that low expressions of Per1 and Per2 were also correlated with poor overall survival of cancers (Per1: HR=1.35, 95%CI: 1.06∼1.72, P=0.014; Per2: HR=1.43, 95%CI: 1.10∼1.85, P=0.007). Subgroup analysis indicated that low Per1 and Per2 expressions were especially associated with poor prognosis of gastrointestinal caners (Per1: HR=1.33, 95%CI: 1.14∼1.55, Ρ<0.001, Ι2=4.2%; Per2: HR=1.62, 95%CI: 1.25∼2.18, P<0.001, I2=0.0%). Conclusions Our study suggested that low Per1, Per2 and Npas2 expression played a distinct and crucial role in progression of cancers. Low expressions of Per1 and Per2 could serve as unfavorable indicators for cancers prognosis, especially for gastrointestinal cancers.
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Affiliation(s)
- Jiangguo Zhang
- Department of Gastroenterology, Shekou People’s Hospital, Shenzhen, Guangdong, China
- * E-mail: (JZ); (WW)
| | - Hong Lv
- Department of Gastroenterology, Shekou People’s Hospital, Shenzhen, Guangdong, China
| | - Mingzhu Ji
- Department of Gastroenterology, Shekou People’s Hospital, Shenzhen, Guangdong, China
| | - Zhimo Wang
- Department of Gastroenterology, Nanshan People’s Hospital, Shenzhen, Guangdong, China
| | - Wenqing Wu
- Shekou People’s Hospital, Shenzhen, Guangdong, China
- * E-mail: (JZ); (WW)
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Liu H, Gong X, Yang K. Overexpression of the clock gene Per2 suppresses oral squamous cell carcinoma progression by activating autophagy via the PI3K/AKT/mTOR pathway. J Cancer 2020; 11:3655-3666. [PMID: 32284762 PMCID: PMC7150464 DOI: 10.7150/jca.42771] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/04/2020] [Indexed: 12/19/2022] Open
Abstract
The current studies reveal that the clock gene Per2 is expressed at lower levels in a variety of tumors and plays a significant tumor suppressor role. However, the biological functions and mechanism of Per2 in OSCC (OSCC: oral squamous cell carcinoma) remain unclear. In this study, OSCC cells with stable overexpression or silencing of Per2 were established to explore their biological functions and mechanism in vivo and in vitro. We discovered that the expression of Per2 decreases in OSCC cells. Overexpression of Per2 promoted autophagy and apoptosis in OSCC cells and inhibited proliferation. The opposite results were obtained in Per2-silenced OSCC cells. In Per2-overexpressing OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly reduced and the LC3B II/I ratio was significantly increased. In contrast, in Per2-silenced OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly enhanced and the LC3B II/I ratio was significantly reduced. When the AKT activator SC79 was added to Per2-overexpressing OSCC cells, the increased autophagy, apoptosis and decreased proliferation were significantly rescued. Furthermore, when autophinib, an autophagy inhibitor, was added to Per2-overexpressing OSCC cells, the decreased proliferation and increased apoptosis were significantly restored. An in vivo tumorigenesis assay also confirmed that overexpression of Per2 suppresses the growth of OSCC. In conclusion, our research results demonstrate that Per2 suppresses OSCC progression by motivating autophagy, as well as inhibiting cell proliferation and promoting apoptosis, which were mediated by autophagy, in a PI3K/AKT/mTOR pathway-dependent manner. Per2 could potentially be used as a valuable therapeutic marker for OSCC.
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Affiliation(s)
- Huan Liu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Xiaobao Gong
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China
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Keshvari M, Nejadtaghi M, Hosseini-Beheshti F, Rastqar A, Patel N. Exploring the role of circadian clock gene and association with cancer pathophysiology. Chronobiol Int 2019; 37:151-175. [PMID: 31791146 DOI: 10.1080/07420528.2019.1681440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues.The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock.Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body's internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients.In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns.
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Affiliation(s)
- Mahtab Keshvari
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada
| | - Mahdieh Nejadtaghi
- Department of Medical Genetics, faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Ali Rastqar
- Department of Psychiatry and Neuroscience, Université Laval, Quebec, Canada
| | - Niraj Patel
- Centre de Recherche CERVO, Université Laval, Québec, Canada
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28
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Disruption of the Molecular Circadian Clock and Cancer: An Epigenetic Link. Biochem Genet 2019; 58:189-209. [DOI: 10.1007/s10528-019-09938-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 09/03/2019] [Indexed: 01/08/2023]
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Li HX. The role of circadian clock genes in tumors. Onco Targets Ther 2019; 12:3645-3660. [PMID: 31190867 PMCID: PMC6526167 DOI: 10.2147/ott.s203144] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/10/2019] [Indexed: 12/12/2022] Open
Abstract
Circadian rhythms are generated via variations in the expression of clock genes that are organized into a complex transcriptional–translational autoregulatory network and regulate the diverse physiological and behavioral activities that are required to adapt to periodic environmental changes. Aberrant clock gene expression is associated with a heightened risk of diseases that affect all aspects of human health, including cancers. Within the past several years, a number of studies have indicated that clock genes contribute to carcinogenesis by altering the expression of clock-controlled and tumor-related genes downstream of many cellular pathways. This review comprehensively summarizes how clock genes affect the development of tumors and their prognosis. In addition, the review provides a full description of the current state of oral cancer research that aims to optimize cancer diagnosis and treatment modalities.
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Affiliation(s)
- Han-Xue Li
- Department of Preventive Dentistry, Stomatological Hospital of Chongqing Medical University, Chongqing 400015, People's Republic of China
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30
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Deng F, Yang K. Current Status of Research on the Period Family of Clock Genes in the Occurrence and Development of Cancer. J Cancer 2019; 10:1117-1123. [PMID: 30854119 PMCID: PMC6400694 DOI: 10.7150/jca.29212] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 01/03/2019] [Indexed: 02/06/2023] Open
Abstract
Several physiological activities of organisms are coordinated based on periodic variations of ~24 h, which is called a circadian rhythm. Circadian rhythms, driven by circadian clock genes, play an important role in the regulation of various complex life activities of organisms, in an orderly and coordinated manner. Period (Per)1/2/3 genes are important core clock genes and part of the Per gene family. Current research has demonstrated that the abnormal expression of Per genes and disruption of circadian rhythms can lead to the occurrence and development of cancer; however, the exact mechanism has not yet been elucidated. Further study on this mechanism may lead to the discovery of new, effective therapies for the prevention and treatment of cancer. The present review summarizes the status of current research with regards to the association between the abnormal expression and rhythmic variation of the Per gene family, and carcinogenesis and progression of cancer.
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Affiliation(s)
- Fan Deng
- Department of Oral and Maxillofacial Surgery, The First Affliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China
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31
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Sánchez DI, González-Fernández B, Crespo I, San-Miguel B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma. J Pineal Res 2018; 65:e12506. [PMID: 29770483 DOI: 10.1111/jpi.12506] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 04/17/2018] [Indexed: 01/07/2023]
Abstract
Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg-1 d-1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.
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Affiliation(s)
- Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | - Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | | | | | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María Jesús Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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32
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Wang F, Luo Y, Li C, Chen I. Correlation between Deregulated Expression of PER2 Gene and Degree of Glioma Malignancy. TUMORI JOURNAL 2018. [DOI: 10.1177/1778.19292] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Fan Wang
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen
| | - Yong Luo
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen
| | - Caiyan Li
- Department of Neurosurgery, The Second People's Hospital of Jingmen, Jingmen, China
| | - Ivan Chen
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen
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Mteyrek A, Filipski E, Guettier C, Okyar A, Lévi F. Clock gene Per2 as a controller of liver carcinogenesis. Oncotarget 2018; 7:85832-85847. [PMID: 27494874 PMCID: PMC5349878 DOI: 10.18632/oncotarget.11037] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 07/13/2016] [Indexed: 01/01/2023] Open
Abstract
Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.
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Affiliation(s)
- Ali Mteyrek
- INSERM and Paris Sud University, UMRS 995, Team « Cancer Chronotherapy and Postoperative Liver », Campus CNRS, Villejuif F-94807, France
| | - Elisabeth Filipski
- INSERM and Paris Sud University, UMRS 995, Team « Cancer Chronotherapy and Postoperative Liver », Campus CNRS, Villejuif F-94807, France
| | - Catherine Guettier
- Assistance Publique-Hopitaux de Paris, Department of Medical Oncology and Laboratory of Anatomy and Pathologic Cytology, Hôpital Paul Brousse, Villejuif F-94800, France
| | - Alper Okyar
- Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul, Turkey
| | - Francis Lévi
- INSERM and Paris Sud University, UMRS 995, Team « Cancer Chronotherapy and Postoperative Liver », Campus CNRS, Villejuif F-94807, France.,Assistance Publique-Hopitaux de Paris, Department of Medical Oncology and Laboratory of Anatomy and Pathologic Cytology, Hôpital Paul Brousse, Villejuif F-94800, France.,Warwick Medical School, Cancer Chronotherapy Unit, Coventry, CV4 7AL, United Kingdom
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34
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Zhanfeng N, Chengquan W, Hechun X, Jun W, Lijian Z, Dede M, Wenbin L, Lei Y. Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway. Oncotarget 2017; 7:27350-62. [PMID: 27036047 PMCID: PMC5053655 DOI: 10.18632/oncotarget.8439] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 03/16/2016] [Indexed: 12/21/2022] Open
Abstract
The Period2 (Per2) gene is an essential component of the mammalian circadian clock and is strongly linked to glioma occurrence and its response to radiotherapy. Here, we examined the role of Per2 in the response to X-ray-induced DNA damage in U343 glioma cells and in a mouse cancer model. Following low dose X-ray irradiation, we observed that lowering Per2 expression using RNAi reduces DNA damage and cell death in U343 cells and glioma tissue. Additionally, Per2 was associated with increased TP53 activity and was involved in the DNA damage during TP53-mediated apoptosis. These findings suggest that Per2, a core circadian gene, is not only a tumor suppressor gene but can also be regarded as an upstream regulator of TP53. It thus appears that Per2 is an important inhibitor of tumor growth that acts by increasing TP53 expression, DNA damage repair, and apoptosis.
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Affiliation(s)
- Niu Zhanfeng
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Wang Chengquan
- The People's Hospital of Liaocheng City, Liaocheng, 252000, China
| | - Xia Hechun
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Wang Jun
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhang Lijian
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Ma Dede
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Liu Wenbin
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Yin Lei
- Department of ICU, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
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35
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Montemurro C, Vadrevu S, Gurlo T, Butler AE, Vongbunyong KE, Petcherski A, Shirihai OS, Satin LS, Braas D, Butler PC, Tudzarova S. Cell cycle-related metabolism and mitochondrial dynamics in a replication-competent pancreatic beta-cell line. Cell Cycle 2017; 16:2086-2099. [PMID: 28820316 DOI: 10.1080/15384101.2017.1361069] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cell replication is a fundamental attribute of growth and repair in multicellular organisms. Pancreatic beta-cells in adults rarely enter cell cycle, hindering the capacity for regeneration in diabetes. Efforts to drive beta-cells into cell cycle have so far largely focused on regulatory molecules such as cyclins and cyclin-dependent kinases (CDKs). Investigations in cancer biology have uncovered that adaptive changes in metabolism, the mitochondrial network, and cellular Ca2+ are critical for permitting cells to progress through the cell cycle. Here, we investigated these parameters in the replication-competent beta-cell line INS 832/13. Cell cycle synchronization of this line permitted evaluation of cell metabolism, mitochondrial network, and cellular Ca2+ compartmentalization at key cell cycle stages. The mitochondrial network is interconnected and filamentous at G1/S but fragments during the S and G2/M phases, presumably to permit sorting to daughter cells. Pyruvate anaplerosis peaks at G1/S, consistent with generation of biomass for daughter cells, whereas mitochondrial Ca2+ and respiration increase during S and G2/M, consistent with increased energy requirements for DNA and lipid synthesis. This synchronization approach may be of value to investigators performing live cell imaging of Ca2+ or mitochondrial dynamics commonly undertaken in INS cell lines because without synchrony widely disparate data from cell to cell would be expected depending on position within cell cycle. Our findings also offer insight into why replicating beta-cells are relatively nonfunctional secreting insulin in response to glucose. They also provide guidance on metabolic requirements of beta-cells for the transition through the cell cycle that may complement the efforts currently restricted to manipulating cell cycle to drive beta-cells through cell cycle.
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Affiliation(s)
- Chiara Montemurro
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
| | - Suryakiran Vadrevu
- b Department of Pharmacology and Brehm Diabetes Research Center , University of Michigan , Ann Arbor , MI , USA
| | - Tatyana Gurlo
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
| | - Alexandra E Butler
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
| | - Kenny E Vongbunyong
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
| | - Anton Petcherski
- c Division of Endocrinology, Department of Medicine, David Geffen School of Medicine , University of California, Los Angeles , Los Angeles , CA , USA
| | - Orian S Shirihai
- c Division of Endocrinology, Department of Medicine, David Geffen School of Medicine , University of California, Los Angeles , Los Angeles , CA , USA
| | - Leslie S Satin
- b Department of Pharmacology and Brehm Diabetes Research Center , University of Michigan , Ann Arbor , MI , USA
| | - Daniel Braas
- d Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA ; UCLA Metabolomics Center , University of California, Los Angeles , Los Angeles , CA , USA
| | - Peter C Butler
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
| | - Slavica Tudzarova
- a Larry L. Hillblom Islet Research Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA.,e Jonsson Comprehensive Cancer Center , University of California, Los Angeles, David Geffen School of Medicine , Los Angeles , CA , USA
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Su X, Chen D, Yang K, Zhao Q, Zhao D, Lv X, Ao Y. The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma. Oncol Rep 2017; 38:472-480. [PMID: 28535015 DOI: 10.3892/or.2017.5653] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 05/12/2017] [Indexed: 11/06/2022] Open
Abstract
Low expression of the clock gene PER2 is closely related to carcinogenesis and the development of cancer; however, the mechanism of the low expression of PER2 that led to cell malignant transformation remains unclear. This study used RNA interference (RNAi) technology to silence PER2 in SCC15 human oral squamous cell carcinoma (OSCC) cells. Then it was found that the ability of cancer cell proliferation, migration, and invasion were markedly increased (P<0.05), and the ability of cancer cell apoptosis and the number of cells in G1/G0 phase were markedly reduced (P<0.05) after PER2 knockdown. PER2 knockdown increased the expression of Ki-67, MDM2, c-Myc, Bcl-2, MMP2, and VEGF mRNA (P<0.05), and decreased the expression of p53, Bax, and TIMP-2 mRNA (P<0.05). The in vivo experiments also proved that the tumorigenicity of SCC15 cells was significantly enhanced after PER2 silence (P<0.05). Overall, these results show that PER2 through the regulation of the numerous important downstream tumor-related genes, plays a major role in tumor suppression, and it may be a novel molecular target for cancer treatment.
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Affiliation(s)
- Xiaoli Su
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Dan Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Qin Zhao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Dan Zhao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Xiaoqiang Lv
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Yiran Ao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma. Front Physiol 2017; 8:352. [PMID: 28620312 PMCID: PMC5451860 DOI: 10.3389/fphys.2017.00352] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 05/15/2017] [Indexed: 12/19/2022] Open
Abstract
Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1) and monocarboxylate lactate transporter 1 (MCT-1). Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid) cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U1084, University of PoitiersPoitiers, France
- Laboratoire de Mathématiques et Applications, UMR Centre National de la Recherche Scientifique 7348, Université de PoitiersPoitiers, France
| | | | - Rémy Guillevin
- DACTIM, Laboratoire de Mathématiques et Applications, Université de Poitiers et CHU de Poitiers, UMR Centre National de la Recherche Scientifique 7348, SP2MIFuturoscope, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications, UMR Centre National de la Recherche Scientifique 7348, Université de PoitiersPoitiers, France
- CHU Amiens Picardie, Université Picardie Jules VerneAmiens, France
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Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2. Proc Natl Acad Sci U S A 2016; 113:13516-13521. [PMID: 27834218 DOI: 10.1073/pnas.1607984113] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The circadian clock and cell cycle networks are interlocked on the molecular level, with the core clock loop exerting a multilevel regulatory role over cell cycle components. This is particularly relevant to the circadian factor Period 2 (Per2), which modulates the stability of the tumor suppressor p53 in unstressed cells and transcriptional activity in response to genotoxic stress. Per2 binding prevents Mdm2-mediated ubiquitination of p53 and, therefore, its degradation, and oscillations in the peaks of Per2 and p53 were expected to correspond. However, our findings showed that Per2 and p53 rhythms were significantly out-of-phase relative to each other in cell lysates and in purified cytoplasmic fractions. These seemingly conflicting experimental data motivated the use of a combined theoretical and experimental approach focusing on the role played by Per2 in dictating the phase of p53 oscillations. Systematic modeling of all possible regulatory scenarios predicted that the observed phase relationship between Per2 and p53 could be simulated if (i) p53 was more stable in the nucleus than in the cytoplasm, (ii) Per2 associates to various ubiquitinated forms of p53, and (iii) Per2 mediated p53 nuclear import. These predictions were supported by a sevenfold increase in p53's half-life in the nucleus and by in vitro binding of Per2 to the various ubiquitinated forms of p53. Last, p53's nuclear shuttling was significantly favored by ectopic expression of Per2 and reduced because of Per2 down-regulation. Our combined theoretical/mathematical approach reveals how clock regulatory nodes can be inferred from oscillating time course data.
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Wang Q, Ao Y, Yang K, Tang H, Chen D. Circadian clock gene Per2 plays an important role in cell proliferation, apoptosis and cell cycle progression in human oral squamous cell carcinoma. Oncol Rep 2016; 35:3387-94. [PMID: 27035749 DOI: 10.3892/or.2016.4724] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 02/04/2016] [Indexed: 11/06/2022] Open
Abstract
Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (P<0.05), the mRNA expression levels of p53, p16 and p21 were significantly decreased (P<0.05), cell proliferation was significantly higher (P<0.05), apoptosis was significantly lower (P<0.05) and the number of cells in the G1/G0 phase was significantly decreased (P<0.05). The present study proves that in OSCC, clock gene Per2 plays an important role in cell cycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.
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Affiliation(s)
- Qingqing Wang
- Stomatological Hospital of Chongqing Medical University, Chongqing 400017, P.R. China
| | - Yiran Ao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hong Tang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Dan Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Zhanfeng N, Yanhui L, Zhou F, Shaocai H, Guangxing L, Hechun X. Circadian genes Per1 and Per2 increase radiosensitivity of glioma in vivo. Oncotarget 2016; 6:9951-8. [PMID: 25760074 PMCID: PMC4496409 DOI: 10.18632/oncotarget.3179] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 01/23/2015] [Indexed: 01/09/2023] Open
Abstract
Per1 and Per2 play a key role in regulating the circadian rhythm in mammals. We report here that although both genes were expressed with a circadian rhythm in glioma and normal brain tissue in rats, their expression profiles differed in the two types of tissue. In addition, high expression of Per1 and Per2 in glioma tissue was associated with increased sensitivity to x-irradiation. No such sensitizing effect was observed in normal tissue. Our results suggest that Per1 and Per2 expression may increase the efficacy of radiotherapy against glioma by promoting apoptosis.
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Affiliation(s)
- Niu Zhanfeng
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, China.,Department of Neurosurgery, The Xijing Hospital of The Fourth Miltary Medical University, Xi'an, China
| | - Li Yanhui
- Graduate School of Ningxia Medical University, Yinchuan, China
| | - Fei Zhou
- Department of Neurosurgery, The Xijing Hospital of The Fourth Miltary Medical University, Xi'an, China
| | - Hao Shaocai
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Li Guangxing
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xia Hechun
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China
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Hamilton N, Diaz-de-Cerio N, Whitmore D. Impaired light detection of the circadian clock in a zebrafish melanoma model. Cell Cycle 2016; 14:1232-41. [PMID: 25832911 PMCID: PMC4615116 DOI: 10.1080/15384101.2015.1014146] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The circadian clock controls the timing of the cell cycle in healthy tissues and clock disruption is known to increase tumourigenesis. Melanoma is one of the most rapidly increasing forms of cancer and the precise molecular circadian changes that occur in a melanoma tumor are unknown. Using a melanoma zebrafish model, we have explored the molecular changes that occur to the circadian clock within tumors. We have found disruptions in melanoma clock gene expression due to a major impairment to the light input pathway, with a parallel loss of light-dependent activation of DNA repair genes. Furthermore, the timing of mitosis in tumors is perturbed, as well as the regulation of certain key cell cycle regulators, such that cells divide arhythmically. The inability to co-ordinate DNA damage repair and cell division is likely to promote further tumourigenesis and accelerate melanoma development.
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Affiliation(s)
- Noémie Hamilton
- a Center for Cell and Molecular Dynamics; Department of Cell and Development Biology ; University College London ; London , UK
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Wang F, Li C, Yongluo, Chen L. The Circadian Gene Clock Plays an Important Role in Cell Apoptosis and the DNA Damage Response In Vitro. Technol Cancer Res Treat 2015; 15:480-6. [PMID: 25976934 DOI: 10.1177/1533034615585433] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/30/2015] [Indexed: 12/30/2022] Open
Abstract
The Clock gene, an indispensable component of the circadian clock, not only modulates circadian oscillations but also regulates organismal function. We examined whether silencing the expression of the human Clock gene in glioma cells influences cell growth and induces apoptosis after irradiation. Silencing the expression of Clock in a human glioma cell line (U87MG), but not in a control glioma cell line, resulted in increased apoptosis and cell cycle arrest. Moreover, silencing Clock expression altered the expression of apoptosis-related genes. The protein levels of c-Myc and Cyclin B1 were downregulated, but those of p53 were upregulated, in human Clock-silenced U87MG cells compared with control cells. Our results suggest that the circadian gene human Clock may play an important role in carcinogenesis by inhibiting apoptotic cell death via attenuating proapoptotic signaling.
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Affiliation(s)
- Fan Wang
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen, China
| | - Caiyan Li
- The Center of Cancer Prevention, The Second People's Hospital of Jingmen, Jingmen, China
| | - Yongluo
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen, China
| | - Lvan Chen
- Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen, China
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43
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Magnone MC, Langmesser S, Bezdek AC, Tallone T, Rusconi S, Albrecht U. The Mammalian circadian clock gene per2 modulates cell death in response to oxidative stress. Front Neurol 2015; 5:289. [PMID: 25628599 PMCID: PMC4292776 DOI: 10.3389/fneur.2014.00289] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 12/19/2014] [Indexed: 11/23/2022] Open
Abstract
Living in the earth’s oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS). Here, we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell’s response to oxidative stress. Mouse embryonic fibroblasts (MEFs) containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild-type cells, which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD+ ratio in the mutant cells is reversed by introduction of the wild-type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process.
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Affiliation(s)
- Maria Chiara Magnone
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
| | - Sonja Langmesser
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
| | - April Candice Bezdek
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
| | - Tiziano Tallone
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
| | - Sandro Rusconi
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
| | - Urs Albrecht
- Department of Biology, Division of Biochemistry, University of Fribourg , Fribourg , Switzerland
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Muter J, Lucas ES, Chan YW, Brighton PJ, Moore JD, Lacey L, Quenby S, Lam EWF, Brosens JJ. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells. FASEB J 2015; 29:1603-14. [PMID: 25573754 PMCID: PMC4396614 DOI: 10.1096/fj.14-267195] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 12/10/2014] [Indexed: 01/24/2023]
Abstract
Implantation requires coordinated interactions between the conceptus and surrounding decidual cells, but the involvement of clock genes in this process is incompletely understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK (circadian locomotor output cycles kaput) and brain muscle arnt-like 1 and repressors encoded by PER (Period) and Cryptochrome genes. We show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Down-regulation occurred between 12 and 24 hours following differentiation and coincided with reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter. RNA sequencing revealed that premature inhibition of PER2 by small interfering RNA knockdown leads to a grossly disorganized decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators among the 1121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of 70 midluteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure (Spearman rank test, ρ = −0.3260; P = 0.0046). Thus, PER2 synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression; uncoupling of these events may cause recurrent pregnancy loss.—Muter, J., Lucas, E. S., Chan, Y.-W., Brighton, P. J., Moore, J. D., Lacey, L., Quenby, S., Lam, E. W.-F., Brosens, J. J. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells.
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Affiliation(s)
- Joanne Muter
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Emma S Lucas
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Yi-Wah Chan
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Paul J Brighton
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Jonathan D Moore
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Lauren Lacey
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Siobhan Quenby
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Eric W-F Lam
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
| | - Jan J Brosens
- *Division of Translational & Systems Medicine, Warwick Medical School, and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; and Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom
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Cheng AY, Zhang Y, Mei HJ, Fang S, Ji P, Yang J, Yu L, Guo WC. Construction of a plasmid for overexpression of human circadian gene period2 and its biological activity in osteosarcoma cells. Tumour Biol 2015; 36:3735-43. [DOI: 10.1007/s13277-014-3013-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 12/23/2014] [Indexed: 02/07/2023] Open
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Gotoh T, Vila-Caballer M, Liu J, Schiffhauer S, Finkielstein CV. Association of the circadian factor Period 2 to p53 influences p53's function in DNA-damage signaling. Mol Biol Cell 2014; 26:359-72. [PMID: 25411341 PMCID: PMC4294682 DOI: 10.1091/mbc.e14-05-0994] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Association of the circadian Per2 factor to p53 results in cytosol–nuclear shuttling of the complex and further association to Mdm2. The trimeric complex remains in the nucleus until a genotoxic signal frees p53, allowing for a transcriptional checkpoint response. Circadian period proteins influence cell division and death by associating with checkpoint components, although their mode of regulation has not been firmly established. hPer2 forms a trimeric complex with hp53 and its negative regulator Mdm2. In unstressed cells, this association leads to increased hp53 stability by blocking Mdm2-dependent ubiquitination and transcription of hp53 target genes. Because of the relevance of hp53 in checkpoint signaling, we hypothesize that hPer2 association with hp53 acts as a regulatory module that influences hp53's downstream response to genotoxic stress. Unlike the trimeric complex, whose distribution was confined to the nuclear compartment, hPer2/hp53 was identified in both cytosol and nucleus. At the transcriptional level, a reporter containing the hp21WAF1/CIP1 promoter, a target of hp53, remained inactive in cells expressing a stable form of the hPer2/hp53 complex even when treated with γ-radiation. Finally, we established that hPer2 directly acts on the hp53 node, as checkpoint components upstream of hp53 remained active in response to DNA damage. Quantitative transcriptional analyses of hp53 target genes demonstrated that unbound hp53 was absolutely required for activation of the DNA-damage response. Our results provide evidence of the mode by which the circadian tumor suppressor hPer2 modulates hp53 signaling in response to genotoxic stress.
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Affiliation(s)
- Tetsuya Gotoh
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
| | - Marian Vila-Caballer
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
| | - Jingjing Liu
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
| | - Samuel Schiffhauer
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
| | - Carla V Finkielstein
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061
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Abstract
Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment.
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Affiliation(s)
- Nicole M Kettner
- Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/ Children's Nutrition Research Center, Baylor College of Medicine , Houston, TX , USA
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48
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Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med 2014; 46:233-43. [PMID: 24491143 DOI: 10.3109/07853890.2013.874664] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In the past 20 years both the circadian clock and endoplasmic reticulum (ER) stress signaling have emerged as major players in oncogenesis and cancer development. Although several lines of evidence have established functional links between these two molecular pathways, their interconnection and the subsequent functional implications in cancer development remain to be fully characterized. Herein, we provide an extensive review of the literature depicting the molecular connectivity linking ER stress signaling and the circadian clock and elaborate on the potential use of these functional interactions in cancer therapeutics.
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Affiliation(s)
- Olivier Pluquet
- Institut de Biologie de Lille, CNRS UMR8161/Universités Lille 1 et Lille 2/Institut Pasteur de Lille , 1, rue du Pr. Calmette, BP 447, 59021 Lille , France
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Karantanos T, Theodoropoulos G, Pektasides D, Gazouli M. Clock genes: their role in colorectal cancer. World J Gastroenterol 2014; 20:1986-1992. [PMID: 24587674 PMCID: PMC3934468 DOI: 10.3748/wjg.v20.i8.1986] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 01/06/2014] [Accepted: 01/20/2014] [Indexed: 02/07/2023] Open
Abstract
Clock genes create a complicated molecular time-keeping system consisting of multiple positive and negative feedback loops at transcriptional and translational levels. This circadian system coordinates and regulates multiple cellular procedures implicated in cancer development such as metabolism, cell cycle and DNA damage response. Recent data support that molecules such as CLOCK1, BMAL1 and PER and CRY proteins have various effects on c-Myc/p21 and Wnt/β-catenin pathways and influence multiple steps of DNA damage response playing a critical role in the preservation of genomic integrity in normal and cancer cells. Notably, all these events have already been related to the development and progression of colorectal cancer (CRC). Recent data highlight critical correlations between clock genes' expression and pathogenesis, progression, aggressiveness and prognosis of CRC. Increased expression of positive regulators of this circadian system such as BMAL1 has been related to decrease overall survival while decreased expression of negative regulators such as PER2 and PER3 is connected with poorer differentiation, increased aggressiveness and worse prognosis. The implications of these molecules in DNA repair systems explain their involvement in the development of CRC but at the same time provide us with novel targets for modern therapeutic approaches for patients with advanced CRC.
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Antoch MP, Toshkov I, Kuropatwinski KK, Jackson M. Deficiency in PER proteins has no effect on the rate of spontaneous and radiation-induced carcinogenesis. Cell Cycle 2013; 12:3673-80. [PMID: 24091726 PMCID: PMC3903718 DOI: 10.4161/cc.26614] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
There is a growing body of evidence that components of the circadian clock are involved in modulation of numerous signaling pathways, and that clock deregulation due to environmental or genetic factors contributes to the development of various pathologies, including cancer. Previous work performed in tissue culture and in in vivo mouse models defined mammalian PERIOD proteins as tumor suppressors, although some experimental inconsistencies (the use of mice on mixed genetic background, lack of sexual discrimination) did not allow a definitive conclusion. To address this issue in a systematic way, we performed a detailed analysis comparing the incidence of tumor development after low-dose ionizing radiation in male and female wild-type, Per1−/−, and Per2−/− mice. We showed that in contrast to previous reports deficiency in either Per1 or Per2 genes by itself does not make mice more tumor-prone; moreover, some of the long-term effects of ionizing radiation in Per2-deficient mice are reminiscent more of accelerated aging rather than tumor-prone phenotype. Our histopathological analysis also revealed significant sexual dimorphism both in the rate of radiation-induced tumorigenesis and in the spectrum of tumors developed, which underscores the importance of using sex-matched experimental groups for in vivo studies. Based on our results, we suggest that the role of PER proteins as bona fide tumor suppressors needs to be reevaluated.
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Affiliation(s)
- Marina P Antoch
- Department of Molecular and Cellular Biology; Roswell Park Cancer Institute; Buffalo, NY USA
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