Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

Merlin, J.; Stechly, Laurence; Beaucé, S de; Monté, Didier; Leteurtre, Emmanuelle; Seuningen, Isabelle Van; Huet, Guillemette; Pigny, Pascal

doi:10.1038/onc.2010.631

Cited by 98 publications

(89 citation statements)

References 54 publications

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“…Irrespective of other possible existing mechanisms, in the present study we have demonstrated -to the best of our knowledge, for the first time -that a decrease of galectin-3 plays a role in MUC1 up-regulation, in mammary cancer, suggestive of an indirect contribution to de-adhesion and in accordance to our in vivo observations. So far, the only existing study showing a role for galectin -3 in MUC1's regulation was that of Merlin et al,2011) in which galectin-3 knock-down, in a pancreatic cancer cell line, led to a decrease in MUC1 expression in accordance with their in vivo data from human pancreatic carcinoma where both galectin-3 and MUC1 are overexpressed in primary tumours. Furthermore, our data showing that MUC1 knock-down leads to decreased levels of galectin-3 imply that MUC-1 in turn is able to up-regulate galectin-3.…”

Section: B C D a B Asupporting

confidence: 52%

Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Oliveira¹,

Matos²,

Santos³

et al. 2011

Int. J. Dev. Biol.

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Galectin-3 is involved both in facilitating detachment of cells from primary tumour sites and favouring cancer cell adhesion and survival to anoikis in the blood stream. The mechanisms behind these apparently contradictory roles of the lectin have not yet been resolved. In order to investigate possible interplays between galectin-3 and its ligands underlying their role in the metastatic process, we examined mucin-1 (MUC1) and epidermal growth factor receptor (EGFR), well-known galectin-3 ligands, as well as galectin-3-binding site expression in a series of spontaneous canine malignant mammary tumours (CMMT) and a metastatic CMMT cell line. Despite the fact that CMMT cells expressed MUC1 and EGFR homogeneously over their plasma membrane, intravascular tumour cells, positive for galectin-3, expressed MUC1 and EGFR in a more focal membrane localization. Moreover, MUC1 overexpression in primary CMMT was present in parallel with down-regulation of galectin-3. Furthermore, in the CMT-U27 cell line, galectin-3 knock-down led to increased MUC1 expression, while MUC1 knock-down led to down-regulation of the lectin. Finally, removal of sialic acid from both CMMT and CMT-U27 xenograft samples exposed galectin-3-ligands throughout the tumour tissue, whereas these ligands were only present in galectin-3-positive invading cells in untreated samples. Interestingly indeed, we show that in vessel-invading cells, there is interaction between galectin-3 and the T antigen in vivo. We therefore hypothesized that loss of galectin-3 and sialylation-related masking of its ligands, in conjunction with their overexpression in specific tumour cell subpopulations, are crucial in regulating adhesive/de-adhesive events in the progression and invasive capacity of metastatic cells.

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Section: B C D a B Asupporting

confidence: 52%

Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Oliveira¹,

Matos²,

Santos³

et al. 2011

Int. J. Dev. Biol.

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“…For example, GM3, the ganglioside containing the sialyllactose epitope, has been reported to interact with EGFR and inhibit its kinase activity in a model supplemented with the GM3 glycolipid, and treatment with neuraminidase can rescue the autophosphorylation of EGFR (37). In addition, galectin-3 also can regulate the cellular trafficking and the level of surface EGFR through binding to the glycans on EGFR, and the binding can be blocked by sialylation on EGFR (38,39).…”

Section: Discussionmentioning

confidence: 99%

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Yen

Liu²,

Chen³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

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Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKIsensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKIresistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKIresistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.E pidermal growth factor receptor (EGFR), one of the most studied receptor tyrosine kinases, is a drug target for cancer therapy, because its kinase activity correlates with tumorigenicity (1). Under normal conditions, EGFR forms dimers upon ligand binding and induces kinase activation (2-6). The conformational change of EGFR from tethered to extended form induced by ligand binding involves the exposure of the interface, followed by dimerization, activation, and autophosphorylation (7). The phosphorylation code of EGFR determines the propensity of the downstream signaling network to regulate cell proliferation, survival, migration, and angiogenesis (8, 9).In a significant fraction of patients with nonsmall cell lung cancer (NSCLC), especially patients in Asia and those with the adenocarcinoma subtype, mutations in the kinase domain of EGFR cause constitutive activation and have been identified as an important factor in EGFR dysregulation (10, 11). Particularly, mutation from leucine to arginine at position 858 (L858R) and, less significantly, deletion of exon 19 that eliminates four amino acids (LREA) account for ∼90% of the mutations involved in the constitutive activation of EGFR. These mutations are commonly found in patients with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib (12-14). However, most patients with such mutations show resistance within months after TKI therapy, and >50% of them develop a second EGFR mutation, T790M, which confers TKI resi...

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“…The nuclear receptor is reported to interact with MUC1 and increase the level of chromatin-bound EGF receptor (Bitler et al 2010;Merlin et al 2011). MUC1 is a cell-surface protein that is known to interact with the receptor and promote receptor internalization.…”

Section: Erbb-1mentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

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Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

Cited by 98 publications

References 54 publications

Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Receptor Tyrosine Kinases in the Nucleus

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