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      Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

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          Abstract

          Vacuolar ATPase (V‐ATPase) is an ATP‐dependent H +‐transporter that pumps protons across intracellular and plasma membranes. It consists of a large multi‐subunit protein complex and influences a wide range of cellular processes. This review focuses on emerging evidence for the roles for V‐ATPase in cancer. This includes how V‐ATPase dysregulation contributes to cancer growth, metastasis, invasion and proliferation, and the potential link between V‐ATPase and the development of drug resistance.

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          The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism.

          Chen-Song Zhang, Shi-Bin Jiang, Mengqi Li … (2014)
          AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.
          Article 0 comments Cited 206 times – based on 0 reviews     Review now
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            Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs.

            Elisabetta Iessi, Licia Rivoltini, Christina Marra … (2004)
            Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin. Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.
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              Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.

              Michael Green, Shingo Kihira, Chih Long Liu … (2015)
              Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
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                Author and article information

                Contributors
                Simon J. Crabb:
                ORCID: http://orcid.org/0000-0003-3521-9064
                s.j.crabb@southampton.ac.uk
                Journal
                Journal ID (nlm-ta): Cancer Med
                Journal ID (iso-abbrev): Cancer Med
                Journal ID (doi): 10.1002/(ISSN)2045-7634
                Journal ID (publisher-id): CAM4
                Title: Cancer Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2045-7634
                Publication date (Electronic): 21 June 2018
                Publication date Collection: August 2018
                Volume: 7
                Issue: 8 ( doiID: 10.1002/cam4.2018.7.issue-8 )
                Pages: 3800-3811
                Affiliations
                [ 1 ] Southampton Cancer Research UK Centre University of Southampton Southampton UK
                [ 2 ] Biological Sciences Faculty of Natural and Environmental Sciences University of Southampton Southampton UK
                Author notes
                [*] [* ] Correspondence

                Simon J. Crabb, University of Southampton, Southampton General Hospital, Southampton, UK.

                Email: s.j.crabb@ 123456southampton.ac.uk

                Author information
                http://orcid.org/0000-0003-3521-9064
                Article
                Publisher ID: CAM41594
                DOI: 10.1002/cam4.1594
                PMC ID: 6089187
                PubMed ID: 29926527
                SO-VID: 64f9a211-5b92-4005-85a8-587ce6d7d46e
                Copyright © © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 09 January 2018
                Date revision received : 07 May 2018
                Date accepted : 08 May 2018
                Page count
                Figures: 2, Tables: 1, Pages: 12, Words: 8237
                Funding
                Funded by: Urology Foundation
                Funded by: Cancer Research UK
                Funded by: The Gerald Kerkut Charitable Trust
                Funded by: Wessex Medical Research
                Categories
                Subject: Review
                Subject: Cancer Biology
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id cam41594
                cover-date August 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:13.08.2018

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer,drug resistance,invasion,metastasis,novel therapy,v‐atpase
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer, drug resistance, invasion, metastasis, novel therapy, v‐atpase

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