Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion.

Autor:	Cantero-Recasens G; Renal Physiopathology Group, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain., Alonso-Marañón J; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC Hospital del Mar, Barcelona, Spain., Lobo-Jarne T; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC Hospital del Mar, Barcelona, Spain., Garrido M; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC Hospital del Mar, Barcelona, Spain., Iglesias M; Department of Pathology, Institut Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain., Espinosa L; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC Hospital del Mar, Barcelona, Spain., Malhotra V; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Feb 08; Vol. 11. Date of Electronic Publication: 2022 Feb 08.
DOI:	10.7554/eLife.73926
Abstrakt:	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. Competing Interests: GC, JA, TL, MG, MI, LE No competing interests declared, VM Senior editor, eLife (© 2022, Cantero-Recasens et al.)
Databáze:	MEDLINE
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