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      Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer

      review-article
      Author(s): 1 , 2 , 2 , 3 , 1 , 2 , *
      Publication date (Electronic):
      Journal: Cells
      Publisher: MDPI
      Keywords: TBK1, IKKε, innate immunity, cancer signaling, autophagy, KRAS

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          Abstract

          While primarily studied for their roles in innate immune response, the IκB kinase (IKK)-related kinases TANK-binding kinase 1 (TBK1) and IKKε also promote the oncogenic phenotype in a variety of cancers. Additionally, several substrates of these kinases control proliferation, autophagy, cell survival, and cancer immune responses. Here we review the involvement of TBK1 and IKKε in controlling different cancers and in regulating responses to cancer immunotherapy.

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          Pancreatic cancers require autophagy for tumor growth.

          Shenghong Yang, Xiaoxu Wang, Gianmarco Contino … (2011)
          Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
          Article 0 comments Cited 595 times – based on 0 reviews     Review now
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            Links between metabolism and cancer.

            Chi Dang (2012)
            Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.
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              Recent insights into the function of autophagy in cancer

              Ravi Amaravadi, Alec C Kimmelman, Eileen White (2016)
              In this review, Amaravadi et al. 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. 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.
              Article 0 comments Cited 376 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 15 September 2018
                Publication date Collection: September 2018
                Volume: 7
                Issue: 9
                Electronic Location Identifier: 139
                Affiliations
                [1 ]Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; joel_durand@ 123456med.unc.edu
                [2 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; qing_zhang@ 123456med.unc.edu
                [3 ]Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
                Author notes
                [* ]Correspondence: abaldwin@ 123456med.unc.edu ; Tel.: +1-919-966-3652
                Author information
                https://orcid.org/0000-0002-3464-431X
                https://orcid.org/0000-0002-6595-8995
                Article
                Publisher ID: cells-07-00139
                DOI: 10.3390/cells7090139
                PMC ID: 6162516
                PubMed ID: 30223576
                SO-VID: 95cff184-11d6-4964-bca4-6ad349c62475
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 29 August 2018
                Date accepted : 13 September 2018
                Categories
                Subject: Review

                Keywords: tbk1,ikkε,innate immunity,cancer signaling,autophagy,kras
                Data availability:
                Keywords: tbk1, ikkε, innate immunity, cancer signaling, autophagy, kras

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