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Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerisation

Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerisation
Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerisation
Altered flux through major metabolic pathways is a hallmark of cancer cells, and provides opportunities for therapy. Stem cell-like cancer (SCLC) cells can cause metastasis and therapy resistance. They possess metabolic plasticity, theoretically enabling resistance to therapies targeting a specific metabolic state. The CtBP transcriptional regulators are potential therapeutic targets in highly glycolytic cancer cells, as they are activated by the glycolytic coenzyme NADH. However, SCLC cells commonly exist in an oxidative state with low rates of glycolysis. Metformin inhibits complex I of the mitochondrial electron transport chain; it can kill oxidative SCLC cells, and has anti-cancer activity in patients. SCLC cells can acquire resistance to metformin through increased glycolysis. Given the potential for long-term metformin therapy, we have studied acquired metformin resistance in cells from the claudin-low subtype of breast cancer. Cells cultured for 8 weeks in sub-IC-50 metformin concentration proliferated comparably to untreated cells, and exhibited higher rates of glucose uptake. SCLC cells were enriched in metformin-adapted cultures. These SCLC cells acquired sensitivity to multiple methods of inhibition of CtBP function, including a cyclic peptide inhibitor of NADH-induced CtBP dimerisation. Single cell mRNA sequencing identified a reprogramming of epithelial mesenchymal and stem cell gene expression in the metformin-adapted SCLC cells. These SCLC cells demonstrated an acquired dependency on one of these genes, Tenascin C. Thus, in addition to acquisition of sensitivity to glycolysis-targeting therapeutic strategies, the reprograming of gene expression in the metformin-adapted SCLC cells renders them sensitive to potential therapeutic approaches not directly linked to cell metabolism.
0143-3334
Banerjee, Arindam
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Birts, Charles
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Darley, Matthew
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Parker, Rachel
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Mirnezami, Alexander
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West, Jonathan
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Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406
Beers, Stephen
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Rose-Zerilli, Matthew
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Blaydes, Jeremy
e957f999-fd91-4f77-ad62-5b4ef069b15b
Banerjee, Arindam
7e1217f4-949a-4851-be1a-c597e31a38b9
Birts, Charles
8689ddad-ba47-4ca6-82c5-001315dbd250
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Parker, Rachel
ca68b9e6-b3d4-4246-845f-4636068d479f
Mirnezami, Alexander
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
West, Jonathan
f1c2e060-16c3-44c0-af70-242a1c58b968
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Rose-Zerilli, Matthew
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Blaydes, Jeremy
e957f999-fd91-4f77-ad62-5b4ef069b15b

Banerjee, Arindam, Birts, Charles, Darley, Matthew, Parker, Rachel, Mirnezami, Alexander, West, Jonathan, Cutress, Ramsey, Beers, Stephen, Rose-Zerilli, Matthew and Blaydes, Jeremy (2018) Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerisation. Carcinogenesis. (doi:10.1093/carcin/bgy174). (In Press)

Record type: Article

Abstract

Altered flux through major metabolic pathways is a hallmark of cancer cells, and provides opportunities for therapy. Stem cell-like cancer (SCLC) cells can cause metastasis and therapy resistance. They possess metabolic plasticity, theoretically enabling resistance to therapies targeting a specific metabolic state. The CtBP transcriptional regulators are potential therapeutic targets in highly glycolytic cancer cells, as they are activated by the glycolytic coenzyme NADH. However, SCLC cells commonly exist in an oxidative state with low rates of glycolysis. Metformin inhibits complex I of the mitochondrial electron transport chain; it can kill oxidative SCLC cells, and has anti-cancer activity in patients. SCLC cells can acquire resistance to metformin through increased glycolysis. Given the potential for long-term metformin therapy, we have studied acquired metformin resistance in cells from the claudin-low subtype of breast cancer. Cells cultured for 8 weeks in sub-IC-50 metformin concentration proliferated comparably to untreated cells, and exhibited higher rates of glucose uptake. SCLC cells were enriched in metformin-adapted cultures. These SCLC cells acquired sensitivity to multiple methods of inhibition of CtBP function, including a cyclic peptide inhibitor of NADH-induced CtBP dimerisation. Single cell mRNA sequencing identified a reprogramming of epithelial mesenchymal and stem cell gene expression in the metformin-adapted SCLC cells. These SCLC cells demonstrated an acquired dependency on one of these genes, Tenascin C. Thus, in addition to acquisition of sensitivity to glycolysis-targeting therapeutic strategies, the reprograming of gene expression in the metformin-adapted SCLC cells renders them sensitive to potential therapeutic approaches not directly linked to cell metabolism.

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Accepted/In Press date: 30 November 2018

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Local EPrints ID: 426810
URI: https://eprints.soton.ac.uk/id/eprint/426810
ISSN: 0143-3334
PURE UUID: 61a65481-b0ce-4b70-a309-756825a960d2
ORCID for Arindam Banerjee: ORCID iD orcid.org/0000-0003-2292-4936
ORCID for Charles Birts: ORCID iD orcid.org/0000-0002-0368-8766
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350

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Date deposited: 12 Dec 2018 17:31
Last modified: 14 Mar 2019 01:45

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Contributors

Author: Charles Birts ORCID iD
Author: Matthew Darley
Author: Rachel Parker
Author: Jonathan West
Author: Ramsey Cutress
Author: Stephen Beers
Author: Jeremy Blaydes

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