Abstract
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.
Highlights
Secreted mucins are synthesized in the Endoplasmic Reticulum (ER) and transported to the Golgi apparatus, where they receive extensive O-glycosylation that increases their molecular weight by about 5-fold
To further confirm whether this effect is related to mucins, patients were divided between high (n=73) and low (n=153) MUC5AC expression levels, and we studied the effect of KChIP3 on the disease-free survival (DFS) of patients
Baseline mucin secretion and its regulator KChIP3 have a clear role in the response to chemotherapy of colorectal cancers (CRC) cells, our results indicated that 5-FU+iri. treatment can trigger mucin production
Summary
Secreted mucins are synthesized in the Endoplasmic Reticulum (ER) and transported to the Golgi apparatus, where they receive extensive O-glycosylation that increases their molecular weight by about 5-fold. These heavily glycosylated mucins are packed into specialized micrometre-sized granules where they can reach molecular weights of up to 50 MDa [1, 2]. Treatment with O-glycosylation inhibitors (Benzyl-α-GalNAc) increases the effectiveness of chemotherapy on pancreatic cells overexpressing the transmembrane mucin MUC1 [11] Whether this is due to inhibition of MUC1 glycosylation only or any of the other O-glycosylated proteins is not known. We have studied this question directly in CRC cell lines and organoids derived from a CRC patient and we show that reducing mucin secretion reverses the chemorefractory properties of hypersecretory CRC cells
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