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      NUCKS promotes cell proliferation and suppresses autophagy through the mTOR-Beclin1 pathway in gastric cancer

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          Abstract

          Background

          Nuclear casein kinase and cyclin-dependent kinase substrate (NUCKS), a novel gene first reported in 2001, is a member of the high mobility group (HMG) family. Although very little is known regarding the biological roles of NUCKS, emerging clinical evidence suggests that the NUCKS protein can be used as a biomarker and therapeutic target in various human ailments, including several types of cancer.

          Methods

          We first assessed the potential correlation between NUCKS expression and gastric cancer prognosis. Then functional experiments were conducted to evaluate the effects of NUCKS in cell proliferation, cell cycle, apoptosis and autophagy. Finally, the roles of NUCKS on gastric cancer were examined in vivo.

          Results

          We found that NUCKS was overexpressed in gastric cancer patients with poor prognosis. Through manipulating NUCKS expression, it was observed to be positively associated with cell proliferation in vitro and in vivo. NUCKS knockdown could induce cell cycle arrest and apoptosis. Then further investigation indicated that NUCKS knockdown could also significantly induce a marked increase in autophagy though the mTOR-Beclin1 pathway, which could be was rescued by NUCKS restoration. Moreover, silencing Beclin1 in NUCKS knockdown cells or adding rapamycin in NUCKS-overexpressed cells also confirmed these results.

          Conclusions

          Our findings revealed that NUCKS functions as an oncogene and an inhibitor of autophagy in gastric cancer. Thus, the downregulation or inhibition of NUCKS may be a potential therapeutic strategy for gastric cancer.

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          Most cited references 38

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          Regulation of mTORC1 by amino acids.

          The mechanistic target of rapamycin complex I (mTORC1) is a central regulator of cellular and organismal growth, and hyperactivation of this pathway is implicated in the pathogenesis of many human diseases including cancer and diabetes. mTORC1 promotes growth in response to the availability of nutrients, such as amino acids, which drive mTORC1 to the lysosomal surface, its site of activation. How amino acid levels are communicated to mTORC1 is only recently coming to light by the discovery of a lysosome-based signaling system composed of Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity towards Rags), and folliculin (FLCN) complexes. Increased understanding of this pathway will not only provide insight into growth control but also into the human pathologies triggered by its deregulation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Recent insights into the function of autophagy in cancer.

            Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumor-promoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.
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              Eating oneself and uninvited guests: autophagy-related pathways in cellular defense.

               Beth Levine (2005)
              The eukaryotic cell uses an evolutionarily conserved lysosomal pathway of self-digestion (autophagy) for survival when extracellular nutrients are limited. In this issue of Cell, new evidence indicates that autophagy is used to for survival when intracellular nutrients are limited by growth factor deprivation (Lum et al., 2005). Other recent studies indicate that the autophagy machinery is also used to degrade foreign microbial invaders (xenophagy).
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                Author and article information

                Contributors
                hcui@swu.edu.cn
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                21 September 2020
                21 September 2020
                2020
                : 39
                Affiliations
                [1 ]GRID grid.263906.8, State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, , Southwest University, ; No.2 Tiansheng Road, Beibei District, Chongqing, 400716 China
                [2 ]GRID grid.263906.8, Cancer Center, Reproductive Medicine Center, Medical Research Institute, , Southwest University, ; Chongqing, 400716 China
                [3 ]GRID grid.488200.6, NHC Key Laboratory of Birth Defects and Reproductive Health (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute), ; Chongqing, 400020 China
                [4 ]GRID grid.263906.8, Engineering Research Center for Cancer Biomedical and Translational Medicine, , Southwest University, ; Chongqing, 400716 China
                [5 ]Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing, 400715 China
                [6 ]GRID grid.263906.8, Westa College, , Southwest University, ; Chongqing, 400716 China
                Article
                1696
                10.1186/s13046-020-01696-7
                7504682
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: National Key Research and Development Program of China
                Award ID: 2016YFC1302204
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81972357
                Award ID: 81872071
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005230, Natural Science Foundation of Chongqing;
                Award ID: cstc2019jcyj-zdxmX0033
                Award ID: cstc2018jcyjAX0330
                Award Recipient :
                Funded by: Chongqing University Innovation Team Building Program funded projects
                Award ID: CXTDX201601010
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy

                nucks, autophagy, mtor, beclin1, gastric cancer

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