The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

Probst, Olivia C.; Karayel, Evren; Schida, Nicole; Nimmerfall, Elisabeth; Hehenberger, Elisabeth; Puxbaum, Verena; Mach, Lukas

doi:10.1042/bj20121422

Cited by 13 publications

(14 citation statements)

References 43 publications

(84 reference statements)

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“…Studies have shown that abnormal proliferation, invasion and migration of tumor cells are common conditions in malignant tumors (29–32). Therefore, the ability of tumor invasion and migration is a detrimental biological feature of malignant tumors, and it is also the most prominent clinical manifestation of malignant tumors (33). It has been found that overexpression of STC2 promotes CRC tumorigenesis by activating the AKT/ERK signaling pathway (26).…”

Section: Discussionmentioning

confidence: 99%

Effect of STC2 gene silencing on colorectal cancer cells

Zhou

Fang

et al. 2019

Mol Med Report

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Stanniocalcin 2 (STC2), a secretory glycoprotein hormone, regulates many biological processes including cell proliferation, apoptosis, tumorigenesis and atherosclerosis. However, the effect of STC2 on proliferation, migration and epithelial-mesenchymal transition (EMT) progression in human colorectal cancer (CRC) cells remains poorly understood. The expression level of STC2 was determined by quantitative real-time polymerase chain reaction (qPCR) and western blot analysis. Cell Counting Kit-8 (CCK-8) was used to detect the viability of SW480 cells. The invasion and migration of cells were identified by wound healing and Transwell assays. The mRNA and protein expression levels of β-catenin, matrix metalloproteinase (MMP)-2, MMP-9, E-cadherin and vimentin were assessed by qPCR and western blot analysis. In the present study, it was demonstrated that STC2 was highly expressed in the CRC cell lines. After silencing of STC2 , the cell viability, migration and invasion were significantly reduced. Silencing of STC2 in the CRC Sw480 cells increased the expression of E-cadherin and decreased the expression of vimentin, MMP-2 and MMP-9, compared to those in the normal and empty vector group. Furthermore, the expression of β-catenin in the STC2 gene silenced group was suppressed, and the expression of β-catenin was reversed by Wnt activator, SB216763. These results demonstrated that STC2 participates in the development and progression of CRC by promoting CRC cell proliferation, survival and migration and activating the Wnt/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Effect of STC2 gene silencing on colorectal cancer cells

Zhou

Fang

et al. 2019

Mol Med Report

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“…M6PR is a multifunctional membrane-associated protein involved in trafficking of soluble lysosomal proteins in the cytoplasm and binding of M6P-containing ligands, such as insulinlike growth factor 2 (IGF2; ref. 24). Importantly, it is a receptor for granzyme B (GrzB) secreted by activated cytotoxic T cells (CTL; ref.…”

Section: Introductionmentioning

confidence: 99%

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

Atay

Kwak

Lavilla-Alonso

et al. 2019

Clinical Cancer Research

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Purpose: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAF V600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi.Experimental Design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT.Results: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment.Conclusions: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.

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“…4b). Further, we reconstituted an Igf2r mutant murine SCC-VII squamous cell carcinoma line ( Igf2r KO)27 with either wild-type human IGF2R (IGF2R) or a mutant version inactive for M6P binding (IGF2R*)28. As ricin itself exhibits OMT N-glycan structures29, we used the IGF2R* mutant cell line to exclude possible binding of ricin to IGF2R via M6P.…”

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confidence: 99%

Comparative glycoproteomics of stem cells identifies new players in ricin toxicity

Stadlmann

Taubenschmid

Wenzel

et al. 2017

Nature

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123

106

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Glycosylation, the covalent attachment of carbohydrate structures onto proteins, is the most abundant post-translational modification. Over 50% of human proteins are glycosylated, which alters their activities in diverse fundamental biological processes. Despite the importance of glycosylation in biology, the identification and functional validation of complex glycoproteins has remained largely unexplored. Here we develop a novel quantitative approach to identify intact glycopeptides from comparative proteomic data sets, allowing us not only to infer complex glycan structures but also to directly map them to sites within the associated proteins at the proteome scale. We apply this method to human and mouse embryonic stem cells to illuminate the stem cell glycoproteome. This analysis nearly doubles the number of experimentally confirmed glycoproteins, identifies previously unknown glycosylation sites and multiple glycosylated stemness factors, and uncovers evolutionarily conserved as well as species-specific glycoproteins in embryonic stem cells. The specificity of our method is confirmed using sister stem cells carrying repairable mutations in enzymes required for fucosylation, Fut9 and Slc35c1. Ablation of fucosylation confers resistance to the bioweapon ricin, and we discover proteins that carry a fucosylation-dependent sugar code for ricin toxicity. Mutations disrupting a subset of these proteins render cells ricin resistant, revealing new players that orchestrate ricin toxicity. Our comparative glycoproteomics platform, SugarQb, enables genome-wide insights into protein glycosylation and glycan modifications in complex biological systems.

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The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

Cited by 13 publications

References 43 publications

Effect of STC2 gene silencing on colorectal cancer cells

Effect of STC2 gene silencing on colorectal cancer cells

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

Comparative glycoproteomics of stem cells identifies new players in ricin toxicity

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