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Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion

Fifteen percent of colorectal cancer (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that CRC cells build a barrier to chemotherapeutics by increasing mucins’ secretion. We show that low leve...

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Autores principales: Cantero-Recasens, Gerard, Alonso-Marañón, Josune, Lobo-Jarne, Teresa, Garrido, Marta, Iglesias, Mar, Espinosa, Lluis, Malhotra, Vivek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846583/
https://www.ncbi.nlm.nih.gov/pubmed/35131032
http://dx.doi.org/10.7554/eLife.73926
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author Cantero-Recasens, Gerard
Alonso-Marañón, Josune
Lobo-Jarne, Teresa
Garrido, Marta
Iglesias, Mar
Espinosa, Lluis
Malhotra, Vivek
author_facet Cantero-Recasens, Gerard
Alonso-Marañón, Josune
Lobo-Jarne, Teresa
Garrido, Marta
Iglesias, Mar
Espinosa, Lluis
Malhotra, Vivek
author_sort Cantero-Recasens, Gerard
collection PubMed
description Fifteen percent of colorectal cancer (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that CRC cells build a barrier to chemotherapeutics by increasing mucins’ secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al., 2018), is a risk factor for CRC patients’ relapse in a subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-fluorouracil + irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3-overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. A similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri. increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous CRC cells and other mucinous tumours.
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spelling pubmed-88465832022-02-16 Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion Cantero-Recasens, Gerard Alonso-Marañón, Josune Lobo-Jarne, Teresa Garrido, Marta Iglesias, Mar Espinosa, Lluis Malhotra, Vivek eLife Cell Biology Fifteen percent of colorectal cancer (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that CRC cells build a barrier to chemotherapeutics by increasing mucins’ secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al., 2018), is a risk factor for CRC patients’ relapse in a subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-fluorouracil + irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3-overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. A similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri. increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous CRC cells and other mucinous tumours. eLife Sciences Publications, Ltd 2022-02-08 /pmc/articles/PMC8846583/ /pubmed/35131032 http://dx.doi.org/10.7554/eLife.73926 Text en © 2022, Cantero-Recasens et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Cantero-Recasens, Gerard
Alonso-Marañón, Josune
Lobo-Jarne, Teresa
Garrido, Marta
Iglesias, Mar
Espinosa, Lluis
Malhotra, Vivek
Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title_full Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title_fullStr Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title_full_unstemmed Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title_short Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
title_sort reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846583/
https://www.ncbi.nlm.nih.gov/pubmed/35131032
http://dx.doi.org/10.7554/eLife.73926
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