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Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

Amy K. Holt, Arafath K. Najumudeen, Tracey J. Collard, Hao Li, Laura M. Millett, Ashley J. Hoskin, Danny N. Legge, Eleanor M. H. Mortensson, Dustin J. Flanagan, Nick Jones Orcid Logo, Madhu Kollareddy, Penny Timms, Matthew Hitchings Orcid Logo, James Cronin Orcid Logo, Owen J. Sansom, Ann C. Williams, Emma E. Vincent

Cancer and Metabolism, Volume: 11, Issue: 1

Swansea University Authors: Nick Jones Orcid Logo, Matthew Hitchings Orcid Logo, James Cronin Orcid Logo

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DOI (Published version): 10.1186/s40170-023-00318-y

Abstract

BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is chall...

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Published in: Cancer and Metabolism
ISSN: 2049-3002
Published: Springer Science and Business Media LLC 2023
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As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.</abstract><type>Journal Article</type><journal>Cancer and Metabolism</journal><volume>11</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2049-3002</issnElectronic><keywords>Colorectal cancer, Aspirin, Metabolism, Metabolic reprogramming, CB-839, Glutaminase</keywords><publishedDay>19</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-10-19</publishedDate><doi>10.1186/s40170-023-00318-y</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>AKH and AJH were supported by the James Tudor Foundation; AKH, AJH and EMHM were supported by John and Bridget Maynard; and PT was supported by a PhD studentship from Bowel &amp; Cancer Research. AKH, AJH, EMHM and PT were also supported by the John James Bristol Foundation. DF, TJC, OJS and ACW by an MRC Research Grant (MR/R017247/1). EEV and DNL are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). EEV and TJC are supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). AKN was supported by Cancer Research UK (CRUK) Beatson Institute core funding (A17196, A31287)—awarded to OJS. OJS was supported by CRUK grants (A21139, A12481, A17196 and A31287) and ERC Starting grant (311301). LMM is supported by a CRUK Scotland Centre Grant (CTRQQR-2021\100006).</funders><projectreference/><lastEdited>2024-04-04T16:11:51.6195020</lastEdited><Created>2024-02-06T09:46:28.3444686</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Amy K.</firstname><surname>Holt</surname><order>1</order></author><author><firstname>Arafath K.</firstname><surname>Najumudeen</surname><order>2</order></author><author><firstname>Tracey J.</firstname><surname>Collard</surname><order>3</order></author><author><firstname>Hao</firstname><surname>Li</surname><order>4</order></author><author><firstname>Laura M.</firstname><surname>Millett</surname><order>5</order></author><author><firstname>Ashley J.</firstname><surname>Hoskin</surname><order>6</order></author><author><firstname>Danny N.</firstname><surname>Legge</surname><order>7</order></author><author><firstname>Eleanor M. H.</firstname><surname>Mortensson</surname><order>8</order></author><author><firstname>Dustin J.</firstname><surname>Flanagan</surname><order>9</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>10</order></author><author><firstname>Madhu</firstname><surname>Kollareddy</surname><order>11</order></author><author><firstname>Penny</firstname><surname>Timms</surname><order>12</order></author><author><firstname>Matthew</firstname><surname>Hitchings</surname><orcid>0000-0002-5527-4709</orcid><order>13</order></author><author><firstname>James</firstname><surname>Cronin</surname><orcid>0000-0002-0590-9462</orcid><order>14</order></author><author><firstname>Owen J.</firstname><surname>Sansom</surname><order>15</order></author><author><firstname>Ann C.</firstname><surname>Williams</surname><order>16</order></author><author><firstname>Emma E.</firstname><surname>Vincent</surname><order>17</order></author></authors><documents><document><filename>65574__29882__0f96221692214ac091043640a3fb4ec0.pdf</filename><originalFilename>65574.pdf</originalFilename><uploaded>2024-04-03T11:33:36.7933961</uploaded><type>Output</type><contentLength>5387682</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This article is licensed under a Creative Commons Attribution 4.0 International License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling v2 65574 2024-02-06 Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false be98847c72c14a731c4a6b7bc02b3bcf 0000-0002-5527-4709 Matthew Hitchings Matthew Hitchings true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false 2024-02-06 BMS BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC. Journal Article Cancer and Metabolism 11 1 Springer Science and Business Media LLC 2049-3002 Colorectal cancer, Aspirin, Metabolism, Metabolic reprogramming, CB-839, Glutaminase 19 10 2023 2023-10-19 10.1186/s40170-023-00318-y COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee AKH and AJH were supported by the James Tudor Foundation; AKH, AJH and EMHM were supported by John and Bridget Maynard; and PT was supported by a PhD studentship from Bowel & Cancer Research. AKH, AJH, EMHM and PT were also supported by the John James Bristol Foundation. DF, TJC, OJS and ACW by an MRC Research Grant (MR/R017247/1). EEV and DNL are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). EEV and TJC are supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). AKN was supported by Cancer Research UK (CRUK) Beatson Institute core funding (A17196, A31287)—awarded to OJS. OJS was supported by CRUK grants (A21139, A12481, A17196 and A31287) and ERC Starting grant (311301). LMM is supported by a CRUK Scotland Centre Grant (CTRQQR-2021\100006). 2024-04-04T16:11:51.6195020 2024-02-06T09:46:28.3444686 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Amy K. Holt 1 Arafath K. Najumudeen 2 Tracey J. Collard 3 Hao Li 4 Laura M. Millett 5 Ashley J. Hoskin 6 Danny N. Legge 7 Eleanor M. H. Mortensson 8 Dustin J. Flanagan 9 Nick Jones 0000-0003-4846-5117 10 Madhu Kollareddy 11 Penny Timms 12 Matthew Hitchings 0000-0002-5527-4709 13 James Cronin 0000-0002-0590-9462 14 Owen J. Sansom 15 Ann C. Williams 16 Emma E. Vincent 17 65574__29882__0f96221692214ac091043640a3fb4ec0.pdf 65574.pdf 2024-04-03T11:33:36.7933961 Output 5387682 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng https://creativecommons.org/licenses/by/4.0/
title Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
spellingShingle Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
Nick Jones
Matthew Hitchings
James Cronin
title_short Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
title_full Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
title_fullStr Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
title_full_unstemmed Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
title_sort Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
author_id_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744
be98847c72c14a731c4a6b7bc02b3bcf
9cfd17551c0d1f7438895121e4fbb6e8
author_id_fullname_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
be98847c72c14a731c4a6b7bc02b3bcf_***_Matthew Hitchings
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
author Nick Jones
Matthew Hitchings
James Cronin
author2 Amy K. Holt
Arafath K. Najumudeen
Tracey J. Collard
Hao Li
Laura M. Millett
Ashley J. Hoskin
Danny N. Legge
Eleanor M. H. Mortensson
Dustin J. Flanagan
Nick Jones
Madhu Kollareddy
Penny Timms
Matthew Hitchings
James Cronin
Owen J. Sansom
Ann C. Williams
Emma E. Vincent
format Journal article
container_title Cancer and Metabolism
container_volume 11
container_issue 1
publishDate 2023
institution Swansea University
issn 2049-3002
doi_str_mv 10.1186/s40170-023-00318-y
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
published_date 2023-10-19T16:11:48Z
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score 11.013148

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