Drug resistance related to aberrant glycosylation in colorectal cancer

Very, Ninon; Lefebvre, Tony; Yazidi‐Belkoura, Ikram El

doi:10.18632/oncotarget.22377

Cited by 82 publications

(67 citation statements)

References 179 publications

(218 reference statements)

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“…In addition, developing a compound to increase CD63 protein levels would lead to more effective treatment of melanoma by coadministration with PLX4032. Moreover, aberrant glycosylation related to drug resistance has been recognized in some cancers, including colon and breast cancer (32,33). Recently, new tools were reported to target glycosylated proteins on cancer cells (34) or increase the effects of immune therapy by editing glycans on cancer cells (35).…”

Section: Discussionmentioning

confidence: 99%

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

et al. 2018

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The BRAF inhibitor PLX4032 is effective in treating BRAF‐mutated melanoma; however, because drug resistance develops in most cases, it is critical to develop a new strategy for inhibiting drug‐resistant melanoma growth. The melanoma‐associated membrane glycoprotein CD63 is involved in cell proliferation and metastasis. Here, we found that cell surface CD63 suppresses the proliferation of human melanoma cells and PLX4032‐resistant cells. Endogenous CD63 protein levels were negatively correlated with PLX4032 resistance of human melanoma cell lines. CD63 overexpression in these cells, in which endogenous CD63 levels are low, suppressed cell proliferation under PLX4032 treatment. The cell surface levels and average molecular mass of CD63 were increased with PLX4032 treatment because of the up‐regulated polylactosamine modification caused by induced β1,3‐N‐acetylglucosami‐nyltransferase 2 expression, which is involved in polylactosamine synthesis. Forced cell surface localization of CD63 led to reduced melanoma cell proliferation without PLX4032 treatment. CD63 overexpression in PLX4032‐resistant cells, in which CD63 levels were lower and cell surface polylactosamine levels were higher than those in parental cells, effectively suppressed proliferation. Our study shows the potential of CD63 to sensitize melanoma cells to PLX4032 and to reduce the proliferation of PLX4032‐resistant cells.—Kudo, K., Yoneda, A., Sakiyama, D., Kojima, K., Miyaji, T., Yamazaki, M., Yaita, S., Hyodo, T., Satow, R., Fukami, K. Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032. FASEB J. 33,3851–3869 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

et al. 2018

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“…Glycosylation is one of the most abundant post-translational modification on proteins and more than 80% of human proteins are glycosylated [34]. RON tyrosine kinases are glycoproteins with eight predicted N-glycosylation sites, four in the SEMA domain (Asn66, Asn419 , Asn458 and Asn488) and one on each of the other domains [35,36].…”

Section: Antibodies Target Unglycosylated Ronmentioning

confidence: 99%

Therapeutic anti-cancer activity of antibodies targeting sulfhydryl bond constrained epitopes on unglycosylated RON receptor tyrosine kinase

et al. 2019

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Recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) and its ligand, serum macrophage-stimulating protein (MSP), are well-established oncogenic drivers for tumorigenesis and metastasis. RON is often found to be alternatively spliced resulting in various isoforms that are constitutively active. RON is therefore an attractive target for cancer therapeutics, including small molecular inhibitors and monoclonal antibodies. While small molecule inhibitors of RON may inhibit other protein kinases including the highly similar MET kinase, monoclonal antibodies targeting RON are more specific, potentially inducing fewer side effects. Although anti-RON monoclonal antibody therapies have been developed and tested in clinical trials, they were met with limited success. Cancer cells have been associated with aberrant glycosylation mechanisms. Notably for RON, the loss of N-bisected glycosylation is a direct cause for tumorigenesis and poorer prognosis in cancer patients. Particularly in gastric cancer, aberrant RON glycosylation augments RON activation. Here, we present a novel panel of monoclonal antibodies which potentially widens the specific targeting of not only the glycosylated RON, but also unglycosylated and aberrantly glycosylated RON. Our antibodies can bind strongly to deglycosylated RON from tunicamycin treated cells, recognise RON in IHC/IF and possess superior therapeutic efficacy in RON expressing xenograft tumours. Our most potent antibody in xenograft assays, is directed to the RON alpha chain and targets a sulfhydryl bond constrained epitope that appears to be cryptic in the crystal structure. This establishes the paradigm that such constrained and cryptic epitopes represent good targets for therapeutic antibodies.

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“…Though lot of evidence supporting the important role of glycosylation in inducing metastasis and acquiring drug resistance phenotype, none of the work has yet demonstrated the link that COSMC deletion mediated aberrant glycosylation induces tumorigenesis and metastasis through the induction of EMT and cellular plasticity in epithelial cells. In view of our previous study where we found the importance of COSMC and glycosylation machinery in the malignant phenotype of cancer cells and development of metastasis, and also other documented examples, we hypothesized the possibility of aberrant glycosylation induced cellular phenotypic changes which enable the cells to efficiently invade the ECM and locate to distant organ sites.…”

Section: Discussionmentioning

confidence: 99%

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

Thomas

Sagar

Caffrey

et al. 2019

J Cellular Molecular Medi

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Aberrant expression of Sialyl‐Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O‐glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial‐to‐mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re‐expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O‐glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

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Drug resistance related to aberrant glycosylation in colorectal cancer

Cited by 82 publications

References 179 publications

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

Therapeutic anti-cancer activity of antibodies targeting sulfhydryl bond constrained epitopes on unglycosylated RON receptor tyrosine kinase

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

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