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      Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1 α and GRP78

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          Abstract

          Inhibition of tumour angiogenesis has an important role in antitumour therapy. However, a recent study indicates that antiangiogenesis therapy may lead to glucose-related protein 78 (GRP78) associated antiapoptotic resistance. The present study aims to elucidate the dual effects of plasminogen kringle 5 (K5) on tumour angiogenesis and apoptosis induction by targeting hypoxia-inducible factor 1 α (HIF-1 α) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1 α and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1 α by upregulating von Hippel-Lindau protein under hypoxia, resulting in the reduction of vascular endothelial growth factor and thus suppressing tumour angiogenesis. Furthermore, K5 decreased GRP78 expression via downregulation of phosphorylated extracellular-regulated protein kinase, leading to caspase-7 cleavage and tumour cell apoptosis. Blocking voltage-dependent anion channel abrogated the effects of K5 on both HIF-1 α and GRP78. K5 significantly inhibited the growth of gastric carcinoma xenografts by inhibiting both angiogenesis and apoptosis. The dual effects suggest that K5 might be a promising bio-therapeutic agent in the treatment of gastric cancer, particularly in patients who exhibit the induction of GRP78.

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          Most cited references31

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          Angiogenesis: an organizing principle for drug discovery?

          Angiogenesis--the process of new blood-vessel growth--has an essential role in development, reproduction and repair. However, pathological angiogenesis occurs not only in tumour formation, but also in a range of non-neoplastic diseases that could be classed together as 'angiogenesis-dependent diseases'. By viewing the process of angiogenesis as an 'organizing principle' in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various diseases that are otherwise unrelated to each other.
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            Hypoxia signalling in cancer and approaches to enforce tumour regression.

            Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.
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              Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.

              Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and its potential applications of cancer therapies.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                October 2017
                26 October 2017
                1 October 2017
                : 8
                : 10
                : e3144
                Affiliations
                [1 ]DME Center, Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine , Guangzhou, China
                [2 ]Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China
                [3 ]Department of Reproductive Medicine Center, Key Laboratory for Reproductive Medicine of Guangdong Province, Third Affiliated Hospital of Guangzhou Medical University , 63 Duobao Road, Guangzhou 510150, China
                [4 ]Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University , Guangzhou, China
                [5 ]Cancer Center, Affiliated Hospital of Guangdong Medical College , Zhanjiang, China
                [6 ]Department of Biochemistry, Basic Medical College, Dali College , Dali, China
                [7 ]International Department, The Affiliated High School of South China Normal University , Guangzhou, China
                [8 ]Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma, USA
                [9 ]China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education , Guangzhou, China
                [10 ]Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University) , Guangzhou, China
                Author notes
                [* ]Program of Molecular Medicine, Affiliated Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen University , 74 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China. Tel: +86 20 873 321 28; Fax: +86 20 873 321 28; E-mail: chunkuishao2011@ 123456163.com or gaogq@ 123456mail.sysu.edu.cn or yangxia@ 123456mail.sysu.edu.cn
                [11]

                S Fang, H Hong, and L Li contributed equally to this work.

                Article
                cddis2017528
                10.1038/cddis.2017.528
                5682690
                29072683
                9fe70192-23a9-4872-9409-cc2b4e575f04
                Copyright © 2017 The Author(s)

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 April 2017
                : 13 July 2017
                : 14 July 2017
                Categories
                Original Article

                Cell biology
                Cell biology

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