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...

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Bibliographic Details
Published in:eLife 2022-02, Vol.11
Main Authors: Cantero-Recasens, Gerard, Alonso-Marañón, Josune, Lobo-Jarne, Teresa, Garrido, Marta, Iglesias, Mar, Espinosa, Lluis, Malhotra, Vivek
Format: Article
Language:English
Subjects:
5-Fluorouracil
5-FU+iri
Allergens
Antimetabolites, Antineoplastic - pharmacology
Biomarkers
Cancer
Cell Biology
Cell death
Cell viability
Chemoresistance
Chemotherapy
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - physiopathology
DNA damage
Drug Resistance, Neoplasm - physiology
Fluorouracil
Fluorouracil - pharmacology
Gene Expression Regulation, Neoplastic
HT29 Cells
Humans
Immunosurveillance
Irinotecan
Irinotecan - pharmacology
KChIP3
Kv Channel-Interacting Proteins - genetics
Medical prognosis
Microscopy
Mucin
Mucin 5AC - genetics
Mucin 5AC - metabolism
Mucin-1
Mucins
Mucins - biosynthesis
Mucins - genetics
Mucins - physiology
Na+/Ca2+ exchanger
Neoplasm Recurrence, Local
Organoids
Phenotypes
Potassium channels (voltage-gated)
Repressor Proteins - genetics
Research Advance
Risk Factors
Tumors
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.73926