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Shou S, Liu R, He J, Jiang X, Liu F, Li Y, Zhang X, En G, Pu Z, Hua B, Pang B, Zhang X. Current and projected incidence rates of pancreatic cancer in 43 countries: an analysis of the Cancer Incidence in Five Continents database. BMJ Open Gastroenterol 2025; 12:e001544. [PMID: 39837792 PMCID: PMC11784423 DOI: 10.1136/bmjgast-2024-001544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 11/20/2024] [Indexed: 01/23/2025] Open
Abstract
OBJECTIVE The aetiology of pancreatic cancer is complex, and there is limited research on its incidence. We aimed to investigate the incidence trends of pancreatic cancer in 43 countries and predict trends up to 2030. METHODS The annual incidence of pancreatic cancer was obtained from the Cancer Incidence in Five Continents database, which comprises 108 cancer registries from 43 countries. Based on available data, we calculated age-standardized incidence rates (ASRs) per 100 000 people for 1988-2012. A Bayesian age-period-cohort model was used to predict the number of new cases and incidence rates up to 2030. RESULTS From 1988 to 2012, the global incidence rate of pancreatic cancer showed a continuously increasing trend, with the ASR increasing from 5.89 in 1988 to 6.78 in 2012, representing an overall average annual percentage change of 8.45%. This increasing trend is expected to persist in most selected countries, whereas a few countries are projected to exhibit a declining trend by 2030. CONCLUSION It appears that the future global incidence of pancreatic cancer is on the rise, but the rate of increase varies among different countries, with some showing a declining trend.
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Affiliation(s)
- Songting Shou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rui Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie He
- Department of Health Management, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Xiaochen Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fudong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiyuan Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Geer En
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiqing Pu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baojin Hua
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bo Pang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xing Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Cao Y, Sun J, Wang X, Zhang X, Tian H, Huang L, Huang Z, Zhang Y, Zhang J, Li L, Zhou S. The double-edged nature of nicotine: toxicities and therapeutic potentials. Front Pharmacol 2024; 15:1427314. [PMID: 39206262 PMCID: PMC11350241 DOI: 10.3389/fphar.2024.1427314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
Nicotine is the primary addictive component of cigarette smoke and is associated with various smoking-related diseases. However, recent research has revealed its broader cognitive-enhancing and anti-inflammatory properties, suggesting its potential therapeutic applications in several conditions. This review aims to examine the double-edged nature of nicotine, encompassing its positive and negative effects. We provide a concise overview of the physiochemical properties and pharmacology of nicotine, including insights into nicotine receptors. Therefore, the article is divided into two main sections: toxicity and therapeutic potential. We comprehensively explored nicotine-related diseases, focusing on specific signaling pathways and the underlying mechanisms that contribute to its effects. Furthermore, we addressed the current research challenges and future development perspectives. This review aims to inspire future researchers to explore the full medical potential of nicotine, which holds significant promise for the clinical management of specific diseases.
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Affiliation(s)
- Yun Cao
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Jiali Sun
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, China
| | - Xiaofeng Wang
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Xiaoyu Zhang
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Huijuan Tian
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Lingling Huang
- Department of Obstetrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Ze Huang
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, China
| | - Yaping Zhang
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
- Key Laboratory of Aerosol Analysis Regulation and Biological Effects of Anhui Province, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Jin Zhang
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
| | - Lin Li
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, China
| | - Shun Zhou
- Key Laboratory of Combustion & Pyrolysis Study of CNTC, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
- Key Laboratory of Aerosol Analysis Regulation and Biological Effects of Anhui Province, China Tobacco Anhui Industrial Co., Ltd., Hefei, China
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Sampaio Moura N, Schledwitz A, Alizadeh M, Kodan A, Njei LP, Raufman JP. Cholinergic Mechanisms in Gastrointestinal Neoplasia. Int J Mol Sci 2024; 25:5316. [PMID: 38791353 PMCID: PMC11120676 DOI: 10.3390/ijms25105316] [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: 03/29/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Asha Kodan
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland, Baltimore County, Baltimore, MD 21250, USA;
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD 21201, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Sridhar A, Sekhon VK, Nguyen C, Abushalha K, Tahanan A, Rahbar MH, Jafri SH. Major Stressful Life Events and the Risk of Pancreatic, Head and Neck Cancers: A Case-Control Study. Cancers (Basel) 2024; 16:451. [PMID: 38275892 PMCID: PMC10814511 DOI: 10.3390/cancers16020451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/08/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Major stressful life events have been shown to be associated with an increased risk of lung cancer, breast cancer and the development of various chronic illnesses. The stress response generated by our body results in a variety of physiological and metabolic changes which can affect the immune system and have been shown to be associated with tumor progression. In this study, we aim to determine if major stressful life events are associated with the incidence of head and neck or pancreatic cancer (HNPC). METHODS This is a matched case-control study. Cases (CAs) were HNPC patients diagnosed within the previous 12 months. Controls (COs) were patients without a prior history of malignancy. Basic demographic data information on major stressful life events was collected using the modified Holmes-Rahe stress scale. A total sample of 280 was needed (79 cases, 201 controls) to achieve at least 80% power to detect odds ratios (ORs) of 2.00 or higher at the 5% level of significance. RESULTS From 1 January 2018 to 31 August 2021, 280 patients were enrolled (CA = 79, CO = 201) in this study. In a multivariable logistic regression analysis after controlling for potential confounding variables (including sex, age, race, education, marital status, smoking history), there was no difference between the lifetime prevalence of major stressful event in cases and controls. However, patients with HNPC were significantly more likely to report a major stressful life event within the preceding 5 years when compared to COs (p = 0.01, OR = 2.32, 95% CI, 1.18-4.54). CONCLUSIONS Patients with head, neck and pancreatic cancers are significantly associated with having a major stressful life event within 5 years of their diagnosis. This study highlights the potential need to recognize stressful life events as risk factors for developing malignancies.
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Affiliation(s)
- Arthi Sridhar
- Division of Hematology/Oncology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Vishaldeep Kaur Sekhon
- Division of Geriatric Medicine and Gerontology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Chandler Nguyen
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Kamelah Abushalha
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Amirali Tahanan
- Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (A.T.); (M.H.R.)
| | - Mohammad Hossein Rahbar
- Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (A.T.); (M.H.R.)
| | - Syed Hasan Jafri
- Division of Hematology/Oncology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Joghataei MT, Bakhtiarzadeh F, Dehghan S, Ketabforoush AHME, Golab F, Zarbakhsh S, Ahmadirad N. The role of neurotransmitters in glioblastoma multiforme-associated seizures. Int J Dev Neurosci 2023; 83:677-690. [PMID: 37563091 DOI: 10.1002/jdn.10294] [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: 06/03/2023] [Revised: 07/20/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
GBM, or glioblastoma multiforme, is a brain tumor that poses a great threat to both children and adults, being the primary cause of death related to brain tumors. GBM is often associated with epilepsy, which can be debilitating. Seizures and the development of epilepsy are the primary symptoms that have a severe impact on the quality of life for GBM patients. It is increasingly apparent that the nervous system plays an essential role in the tumor microenvironment for all cancer types, including GBM. In recent years, there has been a growing understanding of how neurotransmitters control the progression of gliomas. Evidence suggests that neurotransmitters and neuromodulators found in the tumor microenvironment play crucial roles in the excitability, proliferation, quiescence, and differentiation of neurons, glial cells, and neural stem cells. The involvement of neurotransmitters appears to play a significant role in various stages of GBM. In this review, the focus is on presenting updated knowledge and emerging ideas regarding the interplay between neurotransmitters and neuromodulators, such as glutamate, GABA, norepinephrine, dopamine, serotonin, adenosine, and their relationship with GBM and the seizures induced by this condition. The review aims to explore the current understanding and provide new insights into the complex interactions between these neurotransmitters and neuromodulators in the context of GBM-related seizures.
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Affiliation(s)
| | - Fatemeh Bakhtiarzadeh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Samaneh Dehghan
- Eye Research Center, The Five Senses Institute, Rasool Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sam Zarbakhsh
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Nooshin Ahmadirad
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
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Carnet Le Provost K, Kepp O, Kroemer G, Bezu L. Trial watch: beta-blockers in cancer therapy. Oncoimmunology 2023; 12:2284486. [PMID: 38126031 PMCID: PMC10732641 DOI: 10.1080/2162402x.2023.2284486] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/13/2023] [Indexed: 12/23/2023] Open
Abstract
Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines directly act on β-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic receptors slows tumor growth, suggesting potential clinical benefits of using β-blockers in cancer therapy. Much of these positive effects of β-blockade are mediated by improved immunosurveillance. The present trial watch summarizes current knowledge from preclinical and clinical studies investigating the anticancer effects of β-blockers either as standalone agents or in combination with conventional antineoplastic treatments or immunotherapy.
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Affiliation(s)
- Killian Carnet Le Provost
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
| | - Oliver Kepp
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
| | - Guido Kroemer
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lucillia Bezu
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
- Gustave Roussy, Département d’anesthésie, Chirurgie et Interventionnel, Villejuif, France
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Holme JA, Vondráček J, Machala M, Lagadic-Gossmann D, Vogel CFA, Le Ferrec E, Sparfel L, Øvrevik J. Lung cancer associated with combustion particles and fine particulate matter (PM 2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR). Biochem Pharmacol 2023; 216:115801. [PMID: 37696458 PMCID: PMC10543654 DOI: 10.1016/j.bcp.2023.115801] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/13/2023]
Abstract
Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM2.5 represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.
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Affiliation(s)
- Jørn A Holme
- Department of Air Quality and Noise, Division of Climate and Environmental Health, Norwegian Institute of Public Health, PO Box PO Box 222 Skøyen, 0213 Oslo, Norway
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 61265 Brno, Czech Republic
| | - Miroslav Machala
- Department of Pharmacology and Toxicology, Veterinary Research Institute, 62100 Brno, Czech Republic
| | - Dominique Lagadic-Gossmann
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Christoph F A Vogel
- Department of Environmental Toxicology and Center for Health and the Environment, University of California, Davis, CA 95616, USA
| | - Eric Le Ferrec
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Lydie Sparfel
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Johan Øvrevik
- Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, PO Box 1066 Blindern, 0316 Oslo, Norway; Division of Climate and Environmental Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, 0213 Oslo, Norway.
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Michalak N, Małecka-Wojciesko E. Modifiable Pancreatic Ductal Adenocarcinoma (PDAC) Risk Factors. J Clin Med 2023; 12:4318. [PMID: 37445352 DOI: 10.3390/jcm12134318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/20/2023] [Accepted: 06/25/2023] [Indexed: 07/15/2023] Open
Abstract
This study aims to summarize the modifiable risk factors for pancreatic ductal adenocarcinoma (PDAC) that have been known for a long time, as well as information from the most recent reports. As a cancer with a late diagnosis and poor prognosis, accurate analysis of PDAC risk factors is warranted. The incidence of this cancer continues to rise, and the five-year survival rate is the lowest with respect to other tumors. The influence of cigarette smoking, alcohol consumption, and chronic pancreatitis in increasing the risk of pancreatic ductal adenocarcinoma is continually being confirmed. There are also newly emerging reports relating to the impact of lifestyle, including physical activity, the gut and oral microbiome, and hepatotropic viruses. A precise understanding of PDAC risk factors can help to identify groups of high-risk patients, and this may contribute to population awareness and education as well as earlier diagnoses with possible better treatment outcomes.
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Affiliation(s)
- Natalia Michalak
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-419 Lodz, Poland
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-419 Lodz, Poland
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Wu JX, Lau ATY, Xu YM. Indoor Secondary Pollutants Cannot Be Ignored: Third-Hand Smoke. TOXICS 2022; 10:363. [PMID: 35878269 PMCID: PMC9316611 DOI: 10.3390/toxics10070363] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/17/2022] [Accepted: 06/24/2022] [Indexed: 02/05/2023]
Abstract
Smoking has been recognized by the World Health Organization (WHO) as the fifth highest threat to humanity. Smoking, a leading disease promoter, is a major risk factor for non-communicable diseases (NCDs) such as cancer, cardiovascular disease, diabetes, and chronic respiratory diseases. NCDs account for 63% of all deaths worldwide. Passive smoking is also a health risk. Globally, more than a third of all people are regularly exposed to harmful smoke. Air pollution is a common global problem in which pollutants emitted into the atmosphere undergo a series of physical or chemical reactions to produce various oxidation products, which are often referred to as secondary pollutants. Secondary pollutants include ozone (O3), sulfur trioxide (SO3), nitrogen dioxide (NO2), and respirable particulate matter (PM). It is worth mentioning that third-hand smoke (THS), formed by the reaction of nicotine with second-hand smoke (SHS) caused by indoor O3 or nitrous acid (HONO), is a major indoor secondary pollutant that cannot be ignored. As a form of indoor air pollution that is relatively difficult to avoid, THS exists in any corner of the environment where smokers live. In this paper, we summarize the important research progress on the main components, detection, and toxicity of THS and look forward to future research directions. Scientific understanding of THS and its hazards will facilitate smoking bans in indoor and public places and raise public concern for how to prevent and remove THS.
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Affiliation(s)
- Jia-Xun Wu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | | | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
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10
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Subhan M, Saji Parel N, Krishna PV, Gupta A, Uthayaseelan K, Uthayaseelan K, Kadari M. Smoking and Pancreatic Cancer: Smoking Patterns, Tobacco Type, and Dose-Response Relationship. Cureus 2022; 14:e26009. [PMID: 35859955 PMCID: PMC9288232 DOI: 10.7759/cureus.26009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2022] [Indexed: 11/29/2022] Open
Abstract
Pancreatic cancer (PC) is the primary cause of cancer death in the United States and Europe. Despite remarkable advances in the molecular understanding of PC and advances in new therapeutic approaches, PC remains a disease with a poor prognosis. Although evidence indicates that long-term smoking is a major cause of PC, the molecular pathways behind smoking-induced PC pathogenesis are not fully understood. Smoking cessation can significantly reduce the occurrence of PC. This review explores the processes underpinning the influence of smoking-related chemicals on fibrosis and inflammation and provides insight into the etiology of PC. In the future, a thorough exploration of the effects of smoking chemicals on the activity of pancreatic stem cells and then on the essential mediators of the association with cancer cells would likely yield new diagnostic targets.
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11
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Chen X, Sheng L, Ma J, Qi D, Li X, Wang Z, Wu Z, Wong L, Huang JH, Wu E, Ma Q, Zhang D. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone provokes progression from chronic pancreatitis to pancreatic intraepithelial neoplasia. iScience 2022; 25:103647. [PMID: 35028532 PMCID: PMC8741524 DOI: 10.1016/j.isci.2021.103647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/02/2021] [Accepted: 12/15/2021] [Indexed: 12/16/2022] Open
Abstract
The risk of pancreatic cancer is higher among people who are cigarette smokers than among non-smokers; however, the action mechanisms of cigarette metabolites are not yet fully understood. In this study, we investigated the effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoking on chronic pancreatitis and pancreatic cancer as well as the biological mechanism of NNK causing malignant transformation. We show that smoking may promote Kras mutation and P16 promoter methylation from clinical samples and NNK markedly facilitates the growth and migration of pancreatic cancer cells via the activation of Sonic Hedgehog signaling. We demonstrate that NNK promotes acinar-to-ductal metastasis and pancreatic intraepithelial neoplasia in rats with chronic pancreatitis, accompanied by desmoplastic reaction and Gli1 overexpression. Together, we here present evidence that NNK provokes the progression of chronic pancreatitis toward pancreatic cancer and highlight potential strategies and targets for early prevention of pancreatic cancer and its therapeutics.
Smoking is positively correlated with Kras mutation and P16 hypermethylation NNK promotes acinar-to-ductal metastasis and preneoplasia lesions in rats NNK promotes desmoplastic reaction and Gli1 expression in chronic pancreatitis NNK facilitates the growth and migration of cancer via Sonic Hedgehog signaling
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Affiliation(s)
- Xin Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Otorhinolaryngology-Head and Neck Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Sheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiguang Ma
- Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dan Qi
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, USA.,Neuroscience Institute, Baylor Scott and White Health, Temple, TX, USA
| | - Xuqi Li
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lucas Wong
- Division of Hematology/Oncology, Baylor Scott and White Health, Temple, TX, USA
| | - Jason H Huang
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, USA.,Neuroscience Institute, Baylor Scott and White Health, Temple, TX, USA.,Department of Surgery, Texas A and M University College of Medicine, Temple, TX, USA
| | - Erxi Wu
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, USA.,Neuroscience Institute, Baylor Scott and White Health, Temple, TX, USA.,Department of Surgery, Texas A and M University College of Medicine, Temple, TX, USA.,Livestrong Cancer Institutes and Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.,Department of Pharmaceutical Sciences, Texas A and M University College of Pharmacy, College Station, TX, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dong Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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12
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Yang R, Zhang Y, Liao X, Yao Y, Huang C, Liu L. The Relationship Between Anti-Hypertensive Drugs and Cancer: Anxiety to be Resolved in Urgent. Front Pharmacol 2020; 11:610157. [PMID: 33381045 PMCID: PMC7768037 DOI: 10.3389/fphar.2020.610157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/18/2020] [Indexed: 02/05/2023] Open
Abstract
Hypertension is the prevailing independent risk factor for cardiovascular disease worldwide. Anti-hypertensive drugs are the common and effective cure for lowering blood pressure in patients with hypertension. However, some large-scale clinical studies have pointed out that long-term ingestion of some oral anti-hypertensive drugs was associated with risks of incident cancer and the survival time. In contrast, other studies argue that anti-hypertensive drugs are not related to the occurrence of cancer, even as a complementary therapy of tumor treatment. To resolve the dispute, numerous recent mechanistic studies using animal models have tried to find the causal link between cancer and different anti-hypertensive drugs. However, the results were often contradictory. Such uncertainties have taken a toll on hypertensive patients. In this review, we will summarize advances of longitudinal studies in the association between anti-hypertensive drugs and related tumor risks that have helped to move the field forward from associative to causative conclusions, in hope of providing a reference for more rigorous and evidence-based clinical research on the topic to guide the clinical decision making.
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Affiliation(s)
- Rong Yang
- Department of International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Yonggang Zhang
- Department of Periodical Press and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyang Liao
- Department of International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Yao
- Department of International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Chuanying Huang
- Department of International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Lixia Liu
- Health Management Center, West China Hospital, Sichuan University, Chengdu, China
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13
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Abstract
Despite extensive research in the pathogenesis, early detection, and therapeutic approaches of pancreatic ductal adenocarcinoma (PDAC), it remains a devastating and incurable disease. As the global incidence and prevalence of PDAC continue to rise, there is a pressing need to place strong emphasis on its prevention. Although it is widely recognized that cigarette smoking, a potentially modifiable risk factor, has been linked to PDAC development, its contribution to prognosis is still uncertain. Moreover, the mechanistic pathways of PDAC progression secondary to smoking are various and lack a summative narration. Herein, we update and summarize the direct and indirect roles cigarette smoking plays on PDAC development, review literature to conclude the impact cigarette smoking has on prognosis, and postulate a comprehensive mechanism for cigarette smoking-induced PDAC.
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14
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Schuller HM. Inhibitory role of G i-coupled receptors on cAMP-driven cancers with focus on opioid receptors in lung adenocarcinoma and its stem cells. VITAMINS AND HORMONES 2019; 111:299-311. [PMID: 31421705 DOI: 10.1016/bs.vh.2019.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The development, progression, metastasis and drug resistance of the most common human cancers are driven by cyclic adenosine monophosphate (cAMP)-signaling downstream of beta-adrenergic receptors (β-Ars) coupled to the stimulatory G-protein Gs. Receptors coupled to the inhibitory G-protein Gi inhibit this signaling cascade by blocking the activation of the enzyme adenylyl cyclase that catalyzes the formation of cAMP and function as the physiological inhibitors of this signaling cascade. Members of the Gi-coupled receptor family widely expressed in the mammalian organism are GABA B receptors (GABAB-Rs) for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), opioid receptors for endogenous opioid peptides and cannabinoid receptors for endogenous cannabinoids. This review summarizes current evidence for the concept that the activation of Gi-receptor signaling by pharmacological and psychological means is a promising tool for the long-term management of cAMP-driven cancers with special emphasis on the inhibitory effects of opioids on lung adenocarcinoma and its stem cells.
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Affiliation(s)
- Hildegard M Schuller
- Department of Biomedical & Diagnostic Science, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States.
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15
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Abstract
This mini-review summarizes current knowledge on similarities and synergism between smoking and psychological stress-induced modulations of growth stimulating and inhibiting regulatory networks in epithelial cells and epithelial cancers with emphasis on cancer stimulating neurotransmitters and their receptors as well as cancer inhibiting γ-aminobutyric acid (GABA) and opioids. Hyperactive cAMP signaling downstream of beta-adrenergic receptors (β-ARs) has been identified as the driving force of most smoking-associated cancers by numerous preclinical studies and psychological stress intensifies these effects while experimental stress reduction inhibits. The integration of cAMP reduction via stress reduction by pharmacological and psychological means such as psychotherapy, relaxation meditation and yoga into any cancer treatment strategy is recommended.
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Affiliation(s)
- Hildegard M Schuller
- Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA
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16
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Muñoz JP, Carrillo-Beltrán D, Aedo-Aguilera V, Calaf GM, León O, Maldonado E, Tapia JC, Boccardo E, Ozbun MA, Aguayo F. Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells. Front Microbiol 2018; 9:3022. [PMID: 30619121 PMCID: PMC6304352 DOI: 10.3389/fmicb.2018.03022] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 11/22/2018] [Indexed: 01/24/2023] Open
Abstract
High-risk human papillomavirus (HR-HPV) infection is not a sufficient condition for cervical cancer development because most infections are benign and naturally cleared. Epidemiological studies revealed that tobacco smoking is a cofactor with HR-HPV for cervical cancer initiation and progression, even though the mechanism by which tobacco smoke cooperates with HR-HPV in this malignancy is poorly understood. As HR-HPV E6/E7 oncoproteins overexpressed in cervical carcinomas colocalize with cigarette smoke components (CSC), in this study we addressed the signaling pathways involved in a potential interaction between both carcinogenic agents. Cervical cancer-derived cell lines, CaSki (HPV16; 500 copies per cell) and SiHa (HPV16; 2 copies per cell), were acutely exposed to CSC at various non-toxic concentrations and we found that E6 and E7 levels were significantly increased in a dose-dependent manner. Using a reporter construct containing the luciferase gene under the control of the full HPV16 long control region (LCR), we also found that p97 promoter activity is dependent on CSC. Non-synonymous mutations in the LCR-resident TPA (12-O-tetradecanoylphorbol 13-acetate)-response elements (TRE) had significantly decreased p97 promoter activation. Phosphoproteomic arrays and specific inhibitors revealed that CSC-mediated E6/E7 overexpression is at least in part reliant on EGFR phosphorylation. In addition, we showed that the PI3K/Akt pathway is crucial for CSC-induced E6/E7 overexpression. Finally, we demonstrated that HPV16 E6/E7 overexpression is mediated by JUN. overexpression, c-Jun phosphorylation and recruitment of this transcription factor to TRE sites in the HPV16 LCR. We conclude that acute exposure to tobacco smoke activates the transcription of HPV16 E6 and E7 oncogenes through p97 promoter activation, which involves the EGFR/PI3K/Akt/C-Jun signaling pathway activation in cervical cancer cells.
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Affiliation(s)
- Juan P Muñoz
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Diego Carrillo-Beltrán
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Víctor Aedo-Aguilera
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Gloria M Calaf
- Center for Advanced Research, Tarapaca University, Arica, Chile.,Center for Radiological Research, Columbia University Medical Center, New York, NY, United States
| | - Oscar León
- Virology Program, Instituto de Ciencias Biomédicas, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Edio Maldonado
- Programa Biología Celular y Molecular, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile
| | - Julio C Tapia
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Enrique Boccardo
- Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Michelle A Ozbun
- Department of Molecular Genetics and Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Francisco Aguayo
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Center for Advanced Research, Tarapaca University, Arica, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
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17
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Tu CY, Cheng FJ, Chen CM, Wang SL, Hsiao YC, Chen CH, Hsia TC, He YH, Wang BW, Hsieh IS, Yeh YL, Tang CH, Chen YJ, Huang WC. Cigarette smoke enhances oncogene addiction to c-MET and desensitizes EGFR-expressing non-small cell lung cancer to EGFR TKIs. Mol Oncol 2018; 12:705-723. [PMID: 29570930 PMCID: PMC5928373 DOI: 10.1002/1878-0261.12193] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 02/13/2018] [Accepted: 02/20/2018] [Indexed: 12/23/2022] Open
Abstract
Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non‐small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke‐derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine‐derived nitrosamine ketone (NNK), reduced the sensitivity of wild‐type EGFR‐expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P‐treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c‐MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c‐MET reduces B[α]P‐induced Akt activation. The CSE‐treated NSCLC cells are sensitive to the c‐MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c‐MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.
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Affiliation(s)
- Chih-Yen Tu
- Department of Life Science, the iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Fang-Ju Cheng
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Chuan-Mu Chen
- Department of Life Science, the iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Shu-Ling Wang
- Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
| | - Yu-Chun Hsiao
- The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan
| | - Chia-Hung Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,Department of Respiratory Therapy, China Medical University, Taichung, Taiwan
| | - Te-Chun Hsia
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,Department of Respiratory Therapy, China Medical University, Taichung, Taiwan.,Hyperbaric Oxygen Therapy Center, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Hao He
- The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan
| | - Bo-Wei Wang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - I-Shan Hsieh
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Yi-Lun Yeh
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Yun-Ju Chen
- Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.,Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.,School of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Wei-Chien Huang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.,The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.,Research Center for New Drug Development, China Medical University, Taichung, Taiwan
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18
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Throm VM, Männle D, Giese T, Bauer AS, Gaida MM, Kopitz J, Bruckner T, Plaschke K, Grekova SP, Felix K, Hackert T, Giese NA, Strobel O. Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and anti-nicotinic factor in pancreatic cancer. Oncotarget 2018; 9:11734-11751. [PMID: 29545933 PMCID: PMC5837762 DOI: 10.18632/oncotarget.24312] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 12/05/2017] [Indexed: 01/18/2023] Open
Abstract
Smoking is associated with increased risk and poorer prognosis of pancreatic ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic receptors, preferentially α7 (CHRNA7) that also binds the endogenous ligand SLURP1 (Secreted Ly-6/uPAR-Related Protein 1). The clinical significance of SLURP1 and its interaction with nicotine in PDAC are unclear. We detected similar levels of SLURP1 in sera from healthy donors and patients with chronic pancreatitis or PDAC; higher preoperative values were associated with significantly better survival in patients with resected tumors. Pancreatic tissue was not a source of circulating SLURP1 but contained diverse CHRNA7-expressing cells, preferentially epithelial and immune, whereas stromal stellate cells and a quarter of the tumor cells lacked CHRNA7. The CHRNA7 mRNA levels were decreased in PDAC, and CHRNA7high-PDAC patients lived longer. In CHRNA7high COLO357 and PANC-1 cultures, opposing activities of SLURP1 (anti-malignant/CHRNA7-dependent) and nicotine (pro-malignant/CHRNA7-infidel) were exerted without reciprocally interfering with receptor binding or downstream signaling. These data suggested that the ligands act independently and abolish each other’s effects through a mechanism resembling functional antagonism. Thus, SLURP1 might represent an inborn anti-PDAC defense being sensitive to and counteracting nicotine. Boosting SLURP1-CHRNA7 interaction might represent a novel strategy for treatment in high-risk individuals, i.e., smokers with pancreatic cancer.
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Affiliation(s)
- Verena M Throm
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - David Männle
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Giese
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Andrea S Bauer
- Department of Functional Genomics, DKFZ, Heidelberg, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Juergen Kopitz
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics/IMBI, University Hospital Heidelberg, Heidelberg, Germany
| | - Konstanze Plaschke
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Svetlana P Grekova
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Klaus Felix
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalia A Giese
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Oliver Strobel
- European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
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19
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He JJ, Zhang WH, Liu SL, Chen YF, Liao CX, Shen QQ, Hu P. Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma. Oncol Lett 2017; 14:3846-3852. [PMID: 28927156 DOI: 10.3892/ol.2017.6653] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 04/13/2017] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma multiforme is the most common and aggressive form of primary malignant brain tumor. Previous evidence demonstrates that β-adrenergic receptors (β-ARs) are closely associated with the occurrence and development of brain tumors. However, the functional role of β-ARs in human glioblastoma and the underlying mechanisms are not fully understood. In the present study, by using the MTT assay, western blotting, and the reverse transcription polymerase chain reaction, it was revealed that isoproterenol (ISO), an agonist of β-ARs, promoted the proliferation of U251 cells but not U87-MG cells, and that this effect was blocked by the β-ARs antagonist propranolol. It was also demonstrated that ISO transiently induced extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, and that blocking the mitogen-activated protein kinase pathway by U0126 inhibited ERK1/2 phosphorylation and suppressed U251 cell proliferation. In addition, β-ARs activation increased the expression of matrix metalloproteinase (MMP) family members MMP-2 and MMP-9 mRNA through ERK1/2 activation. In conclusion, these data suggest that β-ARs induce ERK1/2 phosphorylation, which may in turn increase MMPs expression to promote U251 cell proliferation. These results provide additional insight into the specific roles of β-ARs in glioblastoma.
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Affiliation(s)
- Jing-Jing He
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
| | - Wen-Hua Zhang
- Institute of Life Science, Nanchang University, Nanchang, Jiangxi 330031, P.R. China
| | - Shi-Ling Liu
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
| | - Yi-Fang Chen
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
| | - Chen-Xi Liao
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
| | - Qian-Qing Shen
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
| | - Ping Hu
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
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20
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Zhang D, Lei J, Ma J, Chen X, Sheng L, Jiang Z, Nan L, Xu Q, Duan W, Wang Z, Li X, Wu Z, Wu E, Ma Q, Huo X. β2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Oncotarget 2017; 7:17760-72. [PMID: 26497365 PMCID: PMC4951248 DOI: 10.18632/oncotarget.5677] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 10/06/2015] [Indexed: 12/20/2022] Open
Abstract
Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1α expression and β2-adrenogenic receptor (β2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1α expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1α and ICI118, 551 (a β2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1α stabilizing agent which decreases HIF-1α degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that β2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β2-AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.
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Affiliation(s)
- Dong Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jianjun Lei
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jiguang Ma
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xin Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Liang Sheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhengdong Jiang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ligang Nan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Qinhong Xu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xuqi Li
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Erxi Wu
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiongwei Huo
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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21
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Amin S, Boffetta P, Lucas AL. The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer. Gut Liver 2016; 10:665-71. [PMID: 27563018 PMCID: PMC5003188 DOI: 10.5009/gnl15451] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/08/2015] [Accepted: 12/09/2015] [Indexed: 12/17/2022] Open
Abstract
Survival from pancreatic cancer remains poor. Conventional treatment has resulted in only marginal improvements in survival compared with survival in the previous several decades. Thus, considerable interest has emerged regarding the potential use of common pharmaceutical agents as chemopreventative and chemotherapeutic options. Aspirin, metformin, statins, β-blockers, and bisphosphonates have biologically plausible mechanisms to inhibit pancreatic neoplasia, whereas dipeptidyl-peptidase 4 inhibitors may promote it. Regardless, real-world epidemiological data remain inconclusive. This review examines the hypotheses, evidence, and current state of the literature for each of these medications and their potential roles in the prevention and treatment of pancreatic cancer.
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Affiliation(s)
- Sunil Amin
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY,
USA
| | - Paolo Boffetta
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY,
USA
| | - Aimee L. Lucas
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY,
USA
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22
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Barone E, Corrado A, Gemignani F, Landi S. Environmental risk factors for pancreatic cancer: an update. Arch Toxicol 2016; 90:2617-2642. [PMID: 27538405 DOI: 10.1007/s00204-016-1821-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/04/2016] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.
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Affiliation(s)
- Elisa Barone
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Alda Corrado
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Federica Gemignani
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy
| | - Stefano Landi
- Genetic Unit, Department of Biology, University of Pisa, Via Derna, 1, 56121, Pisa, Italy.
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23
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Srinivasan P, Thrower EC, Gorelick FS, Said HM. Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Am J Physiol Gastrointest Liver Physiol 2016; 310:G874-83. [PMID: 26999808 PMCID: PMC4888549 DOI: 10.1152/ajpgi.00461.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/11/2016] [Indexed: 01/31/2023]
Abstract
Thiamin is essential for normal metabolism in pancreatic acinar cells (PAC) and is obtained from their microenvironment through specific plasma-membrane transporters, converted to thiamin pyrophosphate (TPP) in the cytoplasm, followed by uptake of TPP by mitochondria through the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). TPP is essential for normal mitochondrial function. We examined the effect of long-term/chronic exposure of PAC in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type or transgenic mice carrying the SLC25A19 promoter) of the cigarette smoke toxin, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on the MTPP uptake process. Our in vitro and in vivo findings demonstrate that NNK negatively affects MTPP uptake and reduced expression of MTPPT protein, MTPPT mRNA, and heterogenous nuclear RNA, as well as SLC25A19 promoter activity. The effect of NNK on Slc25a19 transcription was neither mediated by changes in expression of transcriptional factor NFY-1 (known to drive SLC25A19 transcription), nor due to changes in methylation profile of the Slc25a19 promoter. Rather, it appears to be due to changes in histone modifications that involve significant decreases in histone H3K4-trimethylation and H3K9-acetylation (activation markers). The effect of NNK on MTPPT function is mediated through the nonneuronal α7-nicotinic acetylcholine receptor (α7-nAChR), as indicated by both in vitro (using the nAChR antagonist mecamylamine) and in vivo (using an α7-nAchR(-/-) mouse model) studies. These findings demonstrate that chronic exposure of PAC to NNK negatively impacts PAC MTPP uptake. This effect appears to be exerted at the level of Slc25a19 transcription, involve epigenetic mechanism(s), and is mediated through the α7-nAchR.
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Affiliation(s)
- Padmanabhan Srinivasan
- 1Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; ,2Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California;
| | - Edwin C. Thrower
- 3Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut;
| | - Fred S. Gorelick
- 4Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut; and ,5Veterans Affairs Healthcare System, West Haven, Connecticut
| | - Hamid M. Said
- 1Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; ,2Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California;
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Wan C, Gong C, Zhang H, Hua L, Li X, Chen X, Chen Y, Ding X, He S, Cao W, Wang Y, Fan S, Xiao Y, Zhou G, Shen A. β2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression. Cancer Lett 2016; 373:67-76. [PMID: 26803058 DOI: 10.1016/j.canlet.2016.01.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 01/14/2016] [Accepted: 01/15/2016] [Indexed: 02/06/2023]
Abstract
The β2-adrenergic receptor (β2-AR) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression. In this report, we identified poly(rC)-binding protein 2 (PCBP2) as a novel binding partner for β2-AR using immunoprecipitation-mass spectrometry (IP-MS) approach. The association between β2-AR and PCBP2 was verified using reciprocal immunoprecipitation. Importantly, we found significant interaction and co-localization of the two proteins in the presence of β2-AR agonist in Panc-1 and Bxpc3 PDAC cells. β2-AR-induced recruitment of PCBP2 led to augmented protein level of c-myc in PDAC cells, likely as a result of enhanced internal ribosome entry segment (IRES)-mediated translation of c-myc. The activation of β2-AR accelerated cell proliferation and colony formation, while knockdown of PCBP2 or c-myc restrained the effect. Furthermore, overexpression of PCBP2 was observed in human PDAC cell lines and tissue specimens compared to the normal pancreatic ductal epithelial cells and the non-cancerous tissues respectively. Overexpression of β2-AR and PCBP2 was associated with advanced tumor stage and significantly worsened prognosis in patients with PDAC. Our results elucidate a new molecular mechanism by which β2-AR signaling facilitates PDAC progression through triggering PCBP2-dependent c-myc expression.
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MESH Headings
- Adrenergic beta-2 Receptor Agonists/pharmacology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Female
- HEK293 Cells
- Humans
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Neoplasm Staging
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Protein Binding
- Protein Interaction Domains and Motifs
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- RNA Interference
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Receptors, Adrenergic, beta-2/drug effects
- Receptors, Adrenergic, beta-2/genetics
- Receptors, Adrenergic, beta-2/metabolism
- Signal Transduction/drug effects
- Transfection
- Tumor Burden
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Affiliation(s)
- Chunhua Wan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province 226001, China; Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Chen Gong
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Haifeng Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Lu Hua
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Xiaohong Li
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Xudong Chen
- Department of Pathology, Nantong University Cancer Hospital, Nantong, Jiangsu Province 226001, China
| | - Yinji Chen
- National Engineering Lab of Food Storage and Transportation, Nanjing University of Finance and Economics, Nanjing, Jiangsu Province 210023, China
| | - Xiaoling Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Song He
- Department of Pathology, Nantong University Cancer Hospital, Nantong, Jiangsu Province 226001, China
| | - Wei Cao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Yingying Wang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Shaoqing Fan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Ying Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
| | - Aiguo Shen
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province 226001, China.
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25
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Zhao Y. The Oncogenic Functions of Nicotinic Acetylcholine Receptors. JOURNAL OF ONCOLOGY 2016; 2016:9650481. [PMID: 26981122 PMCID: PMC4769750 DOI: 10.1155/2016/9650481] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/05/2015] [Accepted: 11/16/2015] [Indexed: 11/18/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells. Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction. Emerging evidences suggest nAChRs are posited at the central regulatory loops of numerous cell growth and prosurvival signal pathways and also mediate the synthesis and release of stimulatory and inhibitory neurotransmitters induced by their agonists. Thus nAChRs mediated cell signaling plays an important role in stimulating the growth and angiogenic and neurogenic factors and mediating oncogenic signal transduction during cancer development in a cell type specific manner. In this review, we provide an integrated view of nAChRs signaling in cancer, heightening on the oncogenic properties of nAChRs that may be targeted for cancer treatment.
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Affiliation(s)
- Yue Zhao
- Center of Cell biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
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26
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Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells. PLoS One 2015; 10:e0143575. [PMID: 26633299 PMCID: PMC4669105 DOI: 10.1371/journal.pone.0143575] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 11/08/2015] [Indexed: 01/28/2023] Open
Abstract
Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 μM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes.
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Abstract
OBJECTIVE Smoking may affect pharmacokinetics of chemotherapeutic agents and hemodynamics of the smokers, thereby influencing adverse events and efficacy of chemotherapy in patients with pancreatic cancer (PC). The aim of this study was to clarify how smoking totally affected patients with PC receiving current chemotherapy. METHODS We evaluated the impact of smoking status on the performance of chemotherapy and survival in 262 patients with PC including 158 resectable and 104 unresectable PC. RESULTS There were more male and younger patients in current smokers than in nonsmokers. In unresectable PC, current smokers had more metastatic tumors than locally advanced tumors compared with nonsmokers. In current smokers receiving chemotherapy, the baseline white blood cell count, neutrophil count, and hemoglobin concentration were significantly higher in current smokers than in nonsmokers. Furthermore, grades 3 to 4 neutropenia was observed more often in nonsmokers than smokers. On the other hand, the performance and efficacy of the planned adjuvant chemotherapy were similar between smokers and nonsmokers. More importantly, there was no significant difference in overall prognosis between smokers and nonsmokers receiving chemotherapy. CONCLUSIONS Smoking status has no significant impact on the efficacy of current chemotherapy for both resectable and unresectable PC.
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28
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Haniff AJN, Gam LH. Identification of urinary protein biomarkers for tobacco smoking. Biotechnol Appl Biochem 2015; 63:266-72. [DOI: 10.1002/bab.1357] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 01/23/2015] [Indexed: 01/24/2023]
Affiliation(s)
- AJ Nabill Haniff
- School of Pharmaceutical Sciences; Universiti Sains Malaysia; Penang Malaysia
| | - Lay-Harn Gam
- Doping Control Centre; Universiti Sains Malaysia; Penang Malaysia
- School of Pharmaceutical Sciences; Universiti Sains Malaysia; Penang Malaysia
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29
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Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention. Cancers (Basel) 2015; 7:1292-312. [PMID: 26193320 PMCID: PMC4586771 DOI: 10.3390/cancers7030838] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 07/07/2015] [Accepted: 07/13/2015] [Indexed: 12/16/2022] Open
Abstract
The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.
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30
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Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer. Cell Biosci 2014; 4:46. [PMID: 25949795 PMCID: PMC4422219 DOI: 10.1186/2045-3701-4-46] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 07/01/2014] [Indexed: 01/29/2023] Open
Abstract
Cancer is a leading cause of death worldwide. Aberrant promoter hypermethylation of CpG islands associated with tumor suppressor genes can lead to transcriptional silencing and result in tumorigenesis. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and have been reported to be over-expressed in various cancers. This review highlights the current status of transcriptional and post-translational regulation of the DNMT expression and activity with a focus on dysregulation involved in tumorigenesis. The transcriptional up-regulation of DNMT gene expression can be induced by Ras-c-Jun signaling pathway, Sp1 and Sp3 zinc finger proteins and virus oncoproteins. Transcriptional repression on DNMT genes has also been reported for p53, RB and FOXO3a transcriptional regulators and corepressors. In addition, the low expressions of microRNAs 29 family, 143, 148a and 152 are associated with DNMTs overexpression in various cancers. Several important post-translational modifications including acetylation and phosphorylation have been reported to mediate protein stability and activity of the DNMTs especially DNMT1. In this review, we also discuss drugs targeting DNMT protein expression and activation for therapeutic strategy against cancer.
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31
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Li LF, Chan RLY, Lu L, Shen J, Zhang L, Wu WKK, Wang L, Hu T, Li MX, Cho CH. Cigarette smoking and gastrointestinal diseases: the causal relationship and underlying molecular mechanisms (review). Int J Mol Med 2014; 34:372-80. [PMID: 24859303 DOI: 10.3892/ijmm.2014.1786] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 05/20/2014] [Indexed: 12/16/2022] Open
Abstract
Cigarette smoking is an important risk factor for gastrointestinal (GI) disorders, including peptic ulcers, inflammatory bowel diseases, such as Crohn's disease and cancer. In this review, the relationship between smoking and GI disorders and the underlying mechanisms are discussed. It has been demonstrated that cigarette smoking is positively associated with the pathogenesis of peptic ulcers and the delay of ulcer healing. Mechanistic studies have shown that cigarette smoke and its active ingredients can cause mucosal cell death, inhibit cell renewal, decrease blood flow in the GI mucosa and interfere with the mucosal immune system. Cigarette smoking is also an independent risk factor for various types of cancer of the GI tract. In this review, we also summarize the mechanisms through which cigarette smoking induces tumorigenesis and promotes the development of cancer in various sections of the GI tract. These mechanisms include the activation of nicotinic acetylcholine receptors, the formation of DNA adducts, the stimulation of tumor angiogenesis and the modulation of immune responses in the GI mucosa. A full understanding of these pathogenic mechanisms may help us to develop more effective therapies for GI disorders in the future.
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Affiliation(s)
- L F Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - R L Y Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - L Lu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - J Shen
- Institute of Digestive Diseases, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - L Zhang
- Institute of Digestive Diseases, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - W K K Wu
- Institute of Digestive Diseases, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - L Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - T Hu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - M X Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - C H Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
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Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav Immun 2014; 40:40-7. [PMID: 24650449 PMCID: PMC4102665 DOI: 10.1016/j.bbi.2014.02.019] [Citation(s) in RCA: 195] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 02/18/2014] [Accepted: 02/28/2014] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.
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33
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Schuller HM. Impact of neuro-psychological factors on smoking-associated lung cancer. Cancers (Basel) 2014; 6:580-594. [PMID: 24633083 PMCID: PMC3980616 DOI: 10.3390/cancers6010580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 02/14/2014] [Accepted: 02/21/2014] [Indexed: 12/12/2022] Open
Abstract
Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.
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Affiliation(s)
- Hildegard M Schuller
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
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Tang H, Wei P, Duell EJ, Risch HA, Olson SH, Bueno-de-Mesquita HB, Gallinger S, Holly EA, Petersen G, Bracci PM, McWilliams RR, Jenab M, Riboli E, Tjønneland A, Boutron-Ruault MC, Kaaks R, Trichopoulos D, Panico S, Sund M, Peeters PHM, Khaw KT, Amos CI, Li D. Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data. Carcinogenesis 2014; 35:1039-45. [PMID: 24419231 DOI: 10.1093/carcin/bgu010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling $$\left(P=2.12\times 1{0}^{-7}\right)$$ and α-adrenergic signaling $$\left(P=2.52\times 1{0}^{-5}\right)$$ genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.
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Affiliation(s)
- Hongwei Tang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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35
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Srinivasan P, Subramanian VS, Said HM. Effect of the cigarette smoke component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on physiological and molecular parameters of thiamin uptake by pancreatic acinar cells. PLoS One 2013; 8:e78853. [PMID: 24244374 PMCID: PMC3820693 DOI: 10.1371/journal.pone.0078853] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/23/2013] [Indexed: 01/19/2023] Open
Abstract
Thiamin is indispensable for the normal function of pancreatic acinar cells. These cells take up thiamin via specific carrier-mediated process that involves thiamin transporter-1 and -2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3 genes, respectively). In this study we examined the effect of chronic exposure of pancreatic acinar cells in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type and transgenic mice carrying the SLC19A2 and SLC19A3 promoters) to the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on physiological and molecular parameters of the thiamin uptake process. The results show that chronic exposure of 266-6 cells to NNK (3 µM, 24 h) leads to a significant inhibition in thiamin uptake. The inhibition was associated with a significant decrease in the level of expression of THTR-1 and -2 at the protein and mRNA levels as well as in the activity of SLC19A2 and SLC19A3 promoters. Similarly chronic exposure of mice to NNK (IP 10 mg/100 g body weight, three times/week for 2 weeks) leads to a significant inhibition in thiamin uptake by freshly isolated pancreatic acinar cells, as well as in the level of expression of THTR-1 and -2 protein and mRNA. Furthermore, activity of the SLC19A2 and SLC19A3 promoters expressed in transgenic mice were significantly suppressed by chronic exposure to NNK. The effect of NNK on the activity of the SLC19A2 and SLC19A3 promoters was not mediated via changes in their methylation profile, rather it appears to be exerted via an SP1/GG and SP1/GC cis-regulatory elements in these promoters, respectively. These results demonstrate, for the first time, that chronic exposure of pancreatic acinar cells to NNK negatively impacts the physiological and molecular parameters of thiamin uptake by pancreatic acinar cells and that this effect is exerted, at least in part, at the level of transcription of the SLC19A2 and SLC19A3 genes.
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Affiliation(s)
- Padmanabhan Srinivasan
- Department of Medical Research, VA Medical Center, Long Beach, California, United States of America
- Departments of Medicine and Physiology/Biophysics, University of California Irvine, Irvine, California, United States of America
| | - Veedamali S. Subramanian
- Department of Medical Research, VA Medical Center, Long Beach, California, United States of America
- Departments of Medicine and Physiology/Biophysics, University of California Irvine, Irvine, California, United States of America
| | - Hamid M. Said
- Department of Medical Research, VA Medical Center, Long Beach, California, United States of America
- Departments of Medicine and Physiology/Biophysics, University of California Irvine, Irvine, California, United States of America
- * E-mail:
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Lin Q, Wang F, Yang R, Zheng X, Gao H, Zhang P. Effect of chronic restraint stress on human colorectal carcinoma growth in mice. PLoS One 2013; 8:e61435. [PMID: 23585898 PMCID: PMC3621827 DOI: 10.1371/journal.pone.0061435] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Accepted: 03/13/2013] [Indexed: 12/31/2022] Open
Abstract
Stress alters immunological and neuroendocrinological functions. An increasing number of studies indicate that chronic stress can accelerate tumor growth, but its role in colorectal carcinoma (CRC) progression is not well understood. The aim of this study is to investigate the effects of chronic restraint stress (CRS) on CRC cell growth in nude mice and the possible underlying mechanisms. In this study, we showed that CRS increased the levels of plasma catecholamines including epinephrine (E) and norepinephrine (NE), and stimulated the growth of CRC cell-derived tumors in vivo. Treatment with the adrenoceptor (AR) antagonists phentolamine (PHE, α-AR antagonist) and propranolol (PRO, β-AR antagonist) significantly inhibited the CRS-enhanced CRC cell growth in nude mice. In addition, the stress hormones E and NE remarkably enhanced CRC cell proliferation and viability in culture, as well as tumor growth in vivo. These effects were antagonized by the AR antagonists PHE and PRO, indicating that the stress hormone-induced CRC cell proliferation is AR dependent. We also observed that the β-AR antagonists atenolol (ATE, β1- AR antagonist) and ICI 118,551 (ICI, β2- AR antagonist) inhibited tumor cell proliferation and decreased the stress hormone-induced phosphorylation of extracellular signal-regulated kinases-1/2 (ERK1/2) in vitro and in vivo. The ERK1/2 inhibitor U0126 also blocked the function of the stress hormone, suggesting the involvement of ERK1/2 in the tumor-promoting effect of CRS. We conclude that CRS promotes CRC xenograft tumor growth in nude mice by stimulating CRC cell proliferation through the AR signaling-dependent activation of ERK1/2.
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Affiliation(s)
- Qiang Lin
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Feifei Wang
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Rong Yang
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xinmin Zheng
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Huibao Gao
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
- * E-mail: (PZ); (HBG)
| | - Ping Zhang
- Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
- * E-mail: (PZ); (HBG)
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Wenjuan Y, Yujun L, Ceng Y. Association of single nucleotide polymorphisms of β2-adrenergic receptor gene with clinicopathological features of pancreatic carcinoma. Acta Histochem 2013; 115:198-203. [PMID: 22817959 DOI: 10.1016/j.acthis.2012.06.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 06/19/2012] [Accepted: 06/24/2012] [Indexed: 11/16/2022]
Abstract
β2-Adrenoceptor agonists induce pancreatic cancer occurrence and progression through β2-AR. Polymorphisms in β2-AR gene lead to modified sensitivity to agonists and variable tumorigenic potential. In this study, pancreatic carcinoma and non-neoplastic pancreatic tissues were genotyped at codons 16 and 27 by PCR-restriction fragment length polymorphism and DNA sequencing. Expressions of β2-AR, EGFR, VEGF and MMP-2 were detected by immunohistochemistry. The frequencies of genotypes and alleles at codon 16 between pancreatic carcinoma and non-neoplastic pancreatic tissues showed no difference. The genotype frequencies were associated with TNM grade, lymph node metastasis, and one-year survival rate. The allele G at codon 16 frequently appeared in tumors with high TNM grade, lymph node metastasis, poor prognosis, high expression levels of β2-AR, EGFR, VEGF and MMP-2. The genotype and allele frequencies of codon 27 were not associated with clinicopathological features and down-stream protein expressions. Collectively, SNPs of β2-AR gene at codon 16 were associated with the biological behavior of pancreatic carcinoma. The allele G at codon 16 could facilitate the progression and metastasis of pancreatic carcinoma through elevating vascularization and activating the EGFR pathway. SNPs at codon 16 of β2-AR are new useful biomarkers for predicting biological behavior and survival of pancreatic carcinoma and might be used as a new gene therapeutic target.
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Affiliation(s)
- Yu Wenjuan
- Department of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China
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Al-Wadei MH, Al-Wadei HA, Schuller HM. Gamma-amino butyric acid (GABA) prevents the induction of nicotinic receptor-regulated signaling by chronic ethanol in pancreatic cancer cells and normal duct epithelia. Cancer Prev Res (Phila) 2013; 6:139-148. [PMID: 23213073 PMCID: PMC3565079 DOI: 10.1158/1940-6207.capr-12-0388] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChR) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through β-adrenergic receptors (β-AR). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA). Using MTT assays, cell migration assays, Western blotting, immunoassays, and gene knockdown of individual nAChRs in two PDAC cell lines and in immortalized human pancreatic duct epithelial cells, our data show that treatment for seven days with ethanol induced the protein expression and sensitivity of nAChRs α3, α5, and α7 resulting in increased production of noradrenaline and adrenaline, which drive proliferation and migration via cyclic AMP (cAMP)-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells. Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by upregulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitter production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption.
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Affiliation(s)
- Mohammed H. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
| | - Hussein A.N. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
- Sana’a University, Sana’a, Yemen
| | - Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
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Abstract
Tobacco use in cancer patients is associated with increased cancer treatment failure and decreased survival. Nicotine is one of over 7,000 compounds in tobacco smoke and nicotine is the principal chemical associated with addiction. The purpose of this article is to review the tumor promoting activities of nicotine. Nicotine and its metabolites can promote tumor growth through increased proliferation, angiogenesis, migration, invasion, epithelial to mesenchymal transition, and stimulation of autocrine loops associated with tumor growth. Furthermore, nicotine can decrease the biologic effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy. Common mechanisms appear to involve activation of nicotinic acetylcholine receptors and beta-adrenergic receptors leading to downstream activation of parallel signal transduction pathways that facilitate tumor progression and resistance to treatment. Data suggest that nicotine may be an important mechanism by which tobacco promotes tumor development, progression, and resistance to cancer treatment.
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Affiliation(s)
- Graham W. Warren
- Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA and Roswell Park Cancer Institute, Buffalo, NY, USA
- Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA and Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Anurag K. Singh
- Department of Radiation Medicine, Medical University of South Carolina, Charleston, SC, USA and Roswell Park Cancer Institute, Buffalo, NY, USA
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Abstract
Smoking is a major risk factor for chronic pancreatitis and pancreatic cancer. However, the mechanisms through which it causes the diseases remain unknown. In the present manuscript we reviewed the latest knowledge gained on the effect of cigarette smoke and smoking compounds on cell signaling pathways mediating both diseases. We also reviewed the effect of smoking on the pancreatic cell microenvironment including inflammatory cells and stellate cells.
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Affiliation(s)
- Mouad Edderkaoui
- Cedars-Sinai Medical Center & University of California, Los Angeles, USA
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41
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Schuller HM. Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: implications for intervention. Cancer Biomark 2013; 13:133-144. [PMID: 23912485 PMCID: PMC3740448 DOI: 10.3233/cbm-130323] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This review summarizes current preclinical and clinical evidence in support of the hypothesis that smoking and psychological stress have significant cancer promoting effects on non small cell lung cancer and pancreatic cancer via direct and indirect effects on nicotinic receptor-regulated beta-adrenergic signaling. Evidence is provided that targeted pharmacological interference with the resulting hyperactive cAMP-dependent signaling by beta-blockers or by γ-aminobutyric acid as well as positive psychological influences may be highly effective in preventing and improving clinical outcomes of these cancers, provided that appropriate diagnostic protocols are followed to monitor systemic levels of stress neurotransmitters and cAMP.
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Affiliation(s)
- Hildegard M Schuller
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive Knoxville, TN 37996, USA.
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Pham H, Chen M, Takahashi H, King J, Reber HA, Hines OJ, Pandol S, Eibl G. Apigenin inhibits NNK-induced focal adhesion kinase activation in pancreatic cancer cells. Pancreas 2012; 41:1306-15. [PMID: 22889981 PMCID: PMC3479318 DOI: 10.1097/mpa.0b013e31824d64d9] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) activates β-adrenergic receptor (β-AR) signaling through Src/focal adhesion kinases (FAKs)/mitogen-activated protein kinase to modulate proliferation, migration, and survival. Apigenin (4', 5, 7-trihydroxyflavone) is reported to attenuate proliferation and migration of cancer cells. This study was designed to determine the effects of apigenin on NNK-induced procarcinogenesis using human pancreatic cancer cells BxPC-3 and MIA PaCa-2, which express β-AR. METHODS Proliferation and migration were assessed by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and scratch assays. β-AR, FAK/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) expression and activation were assessed by Western blotting and real-time polymerase chain reaction. RESULTS 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone caused a dose- and time-dependent increase in BxPC-3 and MIA PaCa-2 cell proliferation that was inhibited by propranolol or apigenin. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone also stimulated a time-dependent increase in FAK and ERK activation that was suppressed by propranolol or apigenin. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-enhanced gap closure at 24 hours was prevented by either propranolol or apigenin. CONCLUSION Apigenin suppressed the effects of NNK on pancreatic cancer cell proliferation and migration that are mediated through the β-AR and its downstream signals FAK and ERK activation. These findings suggest a therapeutic role for this natural phytochemical in attenuating the procarcinogenic effects of NNK on pancreatic cancer proliferation and migration.
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Affiliation(s)
- Hung Pham
- Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073
| | - Monica Chen
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
| | - Hiroki Takahashi
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
| | - Jonathan King
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
| | - Howard A. Reber
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
| | - Oscar Joe Hines
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
| | - Stephen Pandol
- Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073
| | - Guido Eibl
- Department of Surgery, Hirshberg Translational Pancreatic Cancer Research Laboratory, UCLA Center of Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095
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Al-Wadei MH, Al-Wadei HA, Schuller HM. Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters. Carcinogenesis 2012; 33:1745-1753. [PMID: 22791813 PMCID: PMC3514900 DOI: 10.1093/carcin/bgs229] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 07/03/2012] [Accepted: 07/06/2012] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a mortality rate near 100%. Smoking is a documented risk factor. However, the mechanisms of smoking-associated pancreatic carcinogenesis are poorly understood. We have shown that binding of nicotine to nicotinic acetylcholine receptors (nAChRs) expressing subunits α7, α3 and α5 in PDAC and pancreatic duct epithelial cells in vitro triggered the production of the neurotransmitters noradrenaline and adrenaline by these cells. In turn, this autocrine catecholamine loop significantly stimulated cell proliferation via cyclic adenosine 3',5'-monophosphate-dependent signaling downstream of beta-adrenergic receptors. However, the observed responses only represent acute cellular reactions to single doses of nicotine whereas nicotine exposure in smokers is chronic. Using the PDAC cell lines BxPC-3 and Panc-1 and immortalized pancreatic duct epithelial cell line HPDE6-C7, our current experiments reveal a significant sensitization of the nAChR-driven autocrine catecholamine regulatory loop in cells pre-exposed to nicotine for 7 days. The resulting increase in catecholamine production was associated with significant inductions in the phosphorylation of signaling proteins ERK, CREB, Src and AKT, upregulated protein expression of nAChR subunits α3, α4, α5 and α7 and increased responsiveness to nicotine in 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and cell migration assays. All three cell lines produced the inhibitory neurotransmitter γ-aminobutyric acid, an activity inhibited by gene knockdown of the α4β2nAChR and suppressed by chronic nicotine via receptor desensitization. All of the observed adverse effects of chronic nicotine were reversed by treatment of the cells with γ-aminobutyric acid, suggesting the potential usefulness of this agent for the improvement of PDAC intervention strategies in smokers.
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Affiliation(s)
- Mohammed H. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of TennesseeKnoxville, TN, USAand
| | - Hussein A.N. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of TennesseeKnoxville, TN, USAand
- Sana’a UniversitySana’a, Yemen
| | - Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of TennesseeKnoxville, TN, USAand
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Al-Wadei HAN, Al-Wadei MH, Ullah MF, Schuller HM. Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice. PLoS One 2012; 7:e43376. [PMID: 22916251 PMCID: PMC3420877 DOI: 10.1371/journal.pone.0043376] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 07/23/2012] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is associated with high levels of psychological distress. We have shown that beta-adrenergic receptors (β-ARs), which are activated by stress neurotransmitters, regulate PDAC cells via cyclic AMP (cAMP)-dependent signaling in vitro, that social stress promotes PDAC progression in mouse xenografts and that γ-aminobutyric acid (GABA) inhibits these responses in vitro and in vivo. The targeted inhibition of stress-induced regulatory pathways may abolish the potentially negative impact of psychological stress on clinical outcomes. Our current data show that chronic exposure of PDAC cell lines Panc-1 (activating point mutations in K-ras) and BXPC-3 (no mutations in K-ras) in vitro to the stress neurotransmitter epinephrine at the concentration (15 nM) previously measured in the serum of mice exposed to social stress significantly increased proliferation and migration. These responses were inhibited in a concentration-dependent manner by celecoxib. The effects of celecoxib alone and in combination with γ-aminobutyric acid (GABA) on the progression of subcutaneous mouse xenografts from the cell line (BXPC-3) most responsive to epinephrine were then investigated in the presence and absence of social stress. Cancer-stimulating factors (VEGF & prostaglandin E(2) [PGE(2)]) and levels of cAMP were measured by immunoassays in blood and xenograft tissue. Phosphorylation of the signaling proteins ERK, CREB, Src, and AKT was assessed by ELISA assays and Western blotting. Expression of COX-2, 5-lipoxygenase, and p-5-LOX were determined by semi-quantitative Western blotting. Celecoxib alone significantly inhibited xenograft progression and decreased systemic and tumor VEGF, PGE2, and cAMP as well as phosphorylated signaling proteins in stress-exposed and stress-free mice. These responses were significantly enhanced by co-treatment with GABA. The celecoxib-induced downregulation of COX-2 protein and p-5-LOX was also significantly enhanced by GABA under both experimental conditions. Our findings identify the targeted inhibition of stress-induced pathways as a promising area for more effective cancer intervention in pancreatic cancer.
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Affiliation(s)
- Hussein A. N. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
- Department of Preventive Medicine, Sana’a University, Sana’a, Yemen
| | - Mohammed H. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
| | - Mohammad F. Ullah
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
| | - Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
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Wittel UA, Momi N, Seifert G, Wiech T, Hopt UT, Batra SK. The pathobiological impact of cigarette smoke on pancreatic cancer development (review). Int J Oncol 2012; 41:5-14. [PMID: 22446714 PMCID: PMC3589138 DOI: 10.3892/ijo.2012.1414] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 01/25/2012] [Indexed: 12/13/2022] Open
Abstract
Despite extensive efforts, pancreatic cancer remains incurable. Most risk factors, such as genetic disposition, metabolic diseases or chronic pancreatitis cannot be influenced. By contrast, cigarette smoking, an important risk factor for pancreatic cancer, can be controlled. Despite the epidemiological evidence of the detrimental effects of cigarette smoking with regard to pancreatic cancer development and its unique property of being influenceable, our understanding of cigarette smoke-induced pancreatic carcinogenesis is limited. Current data on cigarette smoke-induced pancreatic carcinogenesis indicate multifactorial events that are triggered by nicotine, which is the major pharmacologically active constituent of tobacco smoke. In addition to nicotine, a vast number of carcinogens have the potential to reach the pancreatic gland, where they are metabolized, in some instances to even more toxic compounds. These metabolic events are not restricted to pancreatic ductal cells. Several studies show that acinar cells are also greatly affected. Furthermore, pancreatic cancer progenitor cells do not only derive from the ductal epithelial lineage, but also from acinar cells. This sheds new light on cigarette smoke-induced acinar cell damage. On this background, our objective is to outline a multifactorial model of tobacco smoke-induced pancreatic carcinogenesis.
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Affiliation(s)
- Uwe A Wittel
- Department of General- and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany.
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Pandol SJ, Apte MV, Wilson JS, Gukovskaya AS, Edderkaoui M. The burning question: why is smoking a risk factor for pancreatic cancer? Pancreatology 2012; 12:344-349. [PMID: 22898636 PMCID: PMC3956306 DOI: 10.1016/j.pan.2012.06.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 06/13/2012] [Accepted: 06/29/2012] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease. The prognosis is poor; less than 5% of those diagnosed are still alive five years after diagnosis, and complete remission is still rare. Tobacco smoking is a major risk factor of pancreatic cancer. However, the mechanism(s) through which it causes the disease remains unknown. Accumulating evidence indicates that carcinogenic compounds in cigarette smoke stimulate pancreatic cancer progression through induction of inflammation and fibrosis which act in concert with genetic factors leading to the inhibition of cell death and stimulation of proliferation resulting in the promotion of the PDAC.
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Affiliation(s)
- Stephen J. Pandol
- Veterans Affairs Greater Los Angeles Healthcare System and University of California Los Angeles, California
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Anna S. Gukovskaya
- Veterans Affairs Greater Los Angeles Healthcare System and University of California Los Angeles, California
| | - Mouad Edderkaoui
- Veterans Affairs Greater Los Angeles Healthcare System and University of California Los Angeles, California
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Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel UA, Batra SK. Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. Carcinogenesis 2012; 33:1617-28. [PMID: 22623649 DOI: 10.1093/carcin/bgs186] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Despite continuous research efforts directed at early diagnosis and treatment of pancreatic cancer (PC), the status of patients affected by this deadly malignancy remains dismal. Its notoriety with regard to lack of early diagnosis and resistance to the current chemotherapeutics is due to accumulating signaling abnormalities. Hoarding experimental and epidemiological evidences have established a direct correlation between cigarette smoking and PC risk. The cancer initiating/promoting nature of cigarette smoke can be attributed to its various constituents including nicotine, which is the major psychoactive component, and several other toxic constituents, such as nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and polycyclic aromatic hydrocarbons. These predominant smoke-constituents initiate a series of oncogenic events facilitating epigenetic alterations, self-sufficiency in growth signals, evasion of apoptosis, sustained angiogenesis, and metastasis. A better understanding of the molecular mechanisms underpinning these events is crucial for the prevention and therapeutic intervention against PC. This review presents various interconnected signal transduction cascades, the smoking-mediated genotoxicity, and genetic polymorphisms influencing the susceptibility for smoking-mediated PC development by modulating pivotal biological aspects such as cell defense/tumor suppression, inflammation, DNA repair, as well as tobacco-carcinogen metabolization. Additionally, it provides a large perspective toward tumor biology and the therapeutic approaches against PC by targeting one or several steps of smoking-mediated signaling cascades.
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Affiliation(s)
- Navneet Momi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
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48
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Schuller HM, Al-Wadei HAN. Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. CURRENT CANCER THERAPY REVIEWS 2012; 8:116-127. [PMID: 23807873 PMCID: PMC3691862 DOI: 10.2174/157339412800675351] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the α7nicotinic acetylcholine receptor (α7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate β-adrenergic receptor (β-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter γ-aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta-blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful.
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Affiliation(s)
- Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennesse, Knoxville, TN, USA
| | - Hussein A. N. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennesse, Knoxville, TN, USA
- Sana'a University, Sana'a, Yemen
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Jensen K, Afroze S, Munshi MK, Guerrier M, Glaser SS. Mechanisms for nicotine in the development and progression of gastrointestinal cancers. TRANSLATIONAL GASTROINTESTINAL CANCER 2012; 1:81-87. [PMID: 22701817 PMCID: PMC3371638 DOI: 10.3978/j.issn.2224-4778.2011.12.01] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Long-term smoking is major risk factor for a variety of cancers, including those of the gastrointestinal (GI) tract. Historically, nicotine and its derivatives are well known for their role in addiction, and have more recently been documented for their carcinogenic role in a number of human cancers. The cellular and molecular pathways activated by nicotine mimic physiological and environmental carcinogenesis in cancers throughout the GI tract potentiating cancer growth and/or inducing the formation of cancer on their own. Thus, it is important to unlock the carcinogenic mechanisms induced by nicotine in these systems, and underscore nicotine's potential as an environmental hazard. This review outlines the specific pathways demonstrated to mediate nicotine's carcinogenic mechanism in the GI tract. The abundance of cell and animal evidence calls for increased epidemiologic and case-control evaluation of nicotine's role in cancer.
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Prins JM, Wang Y. Quantitative proteomic analysis revealed 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone-induced up-regulation of 20S proteasome in cultured human fibroblast cells. J Proteome Res 2012; 11:2347-54. [PMID: 22369695 DOI: 10.1021/pr201088z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK), is a well-known carcinogen. Although the ability of the metabolically activated form of NNK to generate DNA adducts is well established, little is known about the cellular pathways perturbed by NNK in its native state. In this study, we utilized stable isotope labeling by amino acid in cell culture (SILAC), together with mass spectrometry, to assess the perturbation of protein expression in GM00637 human skin fibroblast cells upon NNK exposure. With this approach, we were able to quantify 1412 proteins and 137 of them were with significantly altered expression following NNK exposure, including the up-regulation of all subunits of the 20S proteasome core complex. The up-regulation of the 20S core complex was also reflected by a significant increase in 20S proteasome activities in GM00637, IMR90, and MCF-7 cells upon NNK treatment. Furthermore, the β-adrenergic receptor (β-AR) antagonist propranolol could attenuate significantly the NNK-induced increase in proteasome activity in all the three cell lines, suggesting that up-regulation of the 20S proteasome may be mediated through the β-AR. Additionally, we found that NNK treatment altered the expression levels of other important proteins including mitochondrial proteins, cytoskeleton-associated proteins, and proteins involved in glycolysis and gluconeogenesis. Results from the present study provided novel insights into the cellular mechanisms targeted by NNK.
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Affiliation(s)
- John M Prins
- Department of Chemistry, University of California, Riverside, California 92521-0403, United States
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