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      The ‘N-factors' in pancreatic cancer: functional relevance of NF-κB, NFAT and Nrf2 in pancreatic cancer

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          Abstract

          Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies, with an overall life expectancy of 6 months. Despite considerable advances in the understanding of the molecular mechanisms involved in the carcinogenesis of PDAC, the outcome of the disease was not significantly improved over the last 20 years. Although some achievements in molecular-targeted therapies have been made (that is, targeting the epidermal growth factor receptor by erlotinib), which already entered clinical settings, and despite the promising outcome of the FOLFIRINOX trial, there is an urgent need for improvement of the chemotherapy in this disease. A plethora of molecular alterations are thought to be responsible for the profound chemoresistance, including mutations in oncogenes and tumor suppressors. Besides these classical hallmarks of cancer, the constitutive or inducible activity of transcription factor pathways are characteristic changes in PDAC. Recently, three transcription factors—nuclear factor -κB (NF-κB), nuclear factor of activated T cells (NFAT) and nuclear factor-E2-related factor-2 (Nrf2)—have been shown to be crucial for tumor development and chemoresistance in pancreatic cancer. These transcription factors are key regulators of a variety of genes involved in nearly all aspects of tumorigenesis and resistance against chemotherapeutics and death receptor ligands. Furthermore, the pathways of NF-κB, NFAT and Nrf2 are functional, interacting on several regulatory steps, and, especially, natural compounds such as curcumin interfere with more than one pathway. Thus, targeting these pathways by established inhibitors or new drugs might have great potential to improve the outcome of PDAC patients, most likely in combination with established anticancer drugs. In this article, we summarize recent progress in the characterization of these transcription-factor pathways and their role in PDAC and therapy resistance. We also discuss future concepts for the treatment of PDAC relying on these pathways.

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          Most cited references116

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          Cancer Statistics, 2008

          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
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            The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress.

            A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.
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              Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.

              Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a 'good' transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2-small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.
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                Author and article information

                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group
                2157-9024
                November 2012
                26 November 2012
                1 November 2012
                : 1
                : 11
                : e35
                Affiliations
                [1 ]Laboratory of Molecular Gastroenterology and Hepatology, Department of Internal Medicine I , Kiel, Germany
                [2 ]Division of Molecular Oncology, Institute for Experimental Cancer Research, Comprehensive Cancer Center North , Kiel, Germany
                Author notes
                [* ]Laboratory of Molecular Gastroenterology and Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, Arnold-Heller-Strasse 3 , 24105 Kiel, Germany. E-mail: aarlt@ 1234561med.uni-kiel.de
                [* ]Division of Molecular Oncology, Institute for Experimental Cancer Research, Comprehensive Cancer Center North, UKSH-Campus Kiel, Arnold-Heller-Strasse 3 , 24105 Kiel, Germany. E-mail: hkalthoff@ 123456email.uni-kiel.de
                Article
                oncsis201235
                10.1038/oncsis.2012.35
                3511680
                23552468
                bda4fc1f-489e-4d82-a322-994497888bea
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 02 October 2012
                : 06 October 2012
                Categories
                Review

                Oncology & Radiotherapy
                apoptosis,transcription factor,signal transduction,chemoresistance,pancreatic cancer

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