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      Exosome‐delivered circRNA promotes glycolysis to induce chemoresistance through the miR‐122‐PKM2 axis in colorectal cancer

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          Abstract

          Malignant tumors, including colorectal cancer (CRC), usually rely on ATP generation through aerobic glycolysis for both rapid growth and chemotherapy resistance. The M2 isoform of pyruvate kinase (PKM2) has a key role in catalyzing glycolysis, and PKM2 expression varies even within a single tumor. In this study, we confirmed that expression of PKM2 is heterogeneous in CRC cells, namely high in oxaliplatin‐resistant cells but relatively low in sensitive cells, and found that chemoresistant cells had enhanced glycolysis and ATP production. In addition, we report a PKM2‐dependent mechanism through which chemosensitive cells may gradually transform into chemoresistant cells. The circular RNA hsa_circ_0005963 (termed ciRS‐122 in this study), which was determined to be a sponge for the PKM2‐targeting miR‐122, was positively correlated with chemoresistance. In vitro and in vivo studies showed that exosomes from oxaliplatin‐resistant cells delivered ciRS‐122 to sensitive cells, thereby promoting glycolysis and drug resistance through miR‐122 sponging and PKM2 upregulation. Moreover, si‐ciRS‐122 transported by exosomes could suppress glycolysis and reverse resistance to oxaliplatin by regulating the ciRS‐122–miR‐122–PKM2 pathway in vivo. Exosomes derived from chemoresistant CRC cells could transfer ciRS‐122 across cells and promote glycolysis to reduce drug susceptibility in chemosensitive cells. This intercellular signal delivery suggests a potential novel therapeutic target and establishes a foundation for future clinical applications in drug‐resistant CRC.

          Abstract

          Exosomes from oxaliplatin‐resistant colorectal cancer (CRC) cells transferred ciRS‐122 to oxaliplatin‐sensitive cells, enhancing glycolysis and drug resistance by promoting PKM2 expression. Furthermore, ciRS‐122 targeting through exosome‐delivered small interfering (si)RNA in vivo enhanced the drug response, indicating a novel potential approach for the reversion of oxaliplatin resistance in CRC.

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          Most cited references10

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          Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

          Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR.
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            A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

            Cancer cells are typically subject to profound metabolic alterations, including the Warburg effect wherein cancer cells oxidize a decreased fraction of the pyruvate generated from glycolysis. We show herein that the mitochondrial pyruvate carrier (MPC), composed of the products of the MPC1 and MPC2 genes, modulates fractional pyruvate oxidation. MPC1 is deleted or underexpressed in multiple cancers and correlates with poor prognosis. Cancer cells re-expressing MPC1 and MPC2 display increased mitochondrial pyruvate oxidation, with no changes in cell growth in adherent culture. MPC re-expression exerted profound effects in anchorage-independent growth conditions, however, including impaired colony formation in soft agar, spheroid formation, and xenograft growth. We also observed a decrease in markers of stemness and traced the growth effects of MPC expression to the stem cell compartment. We propose that reduced MPC activity is an important aspect of cancer metabolism, perhaps through altering the maintenance and fate of stem cells. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7

              Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.
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                Author and article information

                Contributors
                yingguoguang163@163.com
                bayi@tjmuch.com
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                24 January 2020
                March 2020
                : 14
                : 3 ( doiID: 10.1002/mol2.v14.3 )
                : 539-555
                Affiliations
                [ 1 ] Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin China
                [ 2 ] Division of Gastroenterology and Hepatology Shanghai Institute of Digestive Disease China
                [ 3 ] Key Laboratory of Gastroenterology and Hepatology Ministry of Health Shanghai Jiao‐Tong University School of Medicine Renji Hospital China
                Author notes
                [*] [* ] Correspondence

                Y. Ba and G. Ying, Tianjin Medical University Cancer Institute and Hospital, Huan Hu Xi Road 18, Tianjin 300060, China

                Tel: +86 022 23340123

                E‐mails: bayi@ 123456tjmuch.com (YB); yingguoguang163@ 123456163.com (GY)

                Author information
                https://orcid.org/0000-0003-4255-6595
                Article
                MOL212629
                10.1002/1878-0261.12629
                7053238
                31901148
                a719998a-9dc3-452b-8b49-70090c648a11
                © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                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
                : 02 October 2019
                : 04 December 2019
                : 02 January 2020
                Page count
                Figures: 6, Tables: 0, Pages: 17, Words: 7901
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81772629
                Award ID: 81602158
                Award ID: 81602156
                Award ID: 81702275
                Award ID: 81802363
                Award ID: 81702431
                Award ID: 81702437
                Award ID: 81772843
                Award ID: 81974374
                Funded by: Demonstrative Research Platform of Clinical Evaluation Technology for New Anticancer Drugs
                Award ID: 2018ZX09201015
                Funded by: Tianjin Science Foundation
                Award ID: 18JCQNJC81900
                Award ID: 18JCYBJC92000
                Award ID: 18JCYBJC25400
                Award ID: 16PTSYJC00170
                Award ID: 18JCYBJC92900
                Funded by: Science & Technology Development Fund of the Tianjin Education Commission for Higher Education
                Award ID: 2018KJ046
                Award ID: 2017KJ227
                Funded by: Postgraduate Innovation Fund of ‘13th Five‐year Comprehensive Investment’, Tianjin Medical University
                Award ID: YJSCX201906
                Funded by: Tianjin Research Innovation Project for Postgraduate Students
                Award ID: 2019YJSB103
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:03.03.2020

                Oncology & Radiotherapy
                aerobic glycolysis,chemoresistance,circrna,exosome,hsa_circ_0005963,pkm2
                Oncology & Radiotherapy
                aerobic glycolysis, chemoresistance, circrna, exosome, hsa_circ_0005963, pkm2

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