Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Legler, Karen; Rosprim, Ricarda; Karius, Tosca; Eylmann, Kathrin; Roßberg, Maila; Wirtz, Ralph M.; Müller, Volkmar; Witzel, Isabell; Schmalfeldt, Barbara; Milde‐Langosch, Karin; Oliveira‐Ferrer, Leticia

doi:10.1038/bjc.2017.472

Cited by 48 publications

(42 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ERAD components acting early in the pathway are the endoplasmic reticulum degradation-enhancing mannosidases (EDEM), committing misfolded glycoproteins to degradation. To date, no EDEM-specific inhibitors are known, and the effects of EDEM inhibition/deletion on cancer cells have not been investigated, although the generic α -mannosidase inhibitor kifunensine [93] increased adhesion of breast cancer cells to endothelial cells [94] and 1-deoxymannojirimycin (another broad-spectrum mannosidase inhibitor) induced cellular ER stress in a human hepatocarcinoma cell line [95].…”

Section: Methodsmentioning

confidence: 99%

“…ER ManIA aka mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (ER ManIA, UniProt P33908, MA1A1_HUMAN)— originally annotated as resident in the Golgi—has been shown to colocalise with ER α Man I in quality control vesicles (QCVs) and is also implicated in targeting to ERAD [103]. In cancer, the enzyme levels showed impact on degradation of cell-surface glycoprotein involved in cell-cell adhesion and metastasis: reduced ER ManIA expression or mannosidase inhibition lead to a significantly increased adhesion of breast cancer cells to endothelial cells [94]. Conversely, ER ManIA was downregulated in metastatic hepatocellular cancer (HCC) cell lines and orthotopic xenograft tumours, in comparison with nonmetastatic HCC controls [104].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Tax

Lia

Santino

et al. 2019

Journal of Oncology

View full text Add to dashboard Cite

Endoplasmic reticulum glycoprotein folding quality control (ERQC) and ER-associated degradation (ERAD) preside over cellular glycoprotein secretion and maintain steady glycoproteostasis. When cells turn malignant, cancer cell plasticity is affected and supported either by point mutations, preferential isoform selection, altered expression levels, or shifts to conformational equilibria of a secreted glycoprotein. Such changes are crucial in mediating altered extracellular signalling, metabolic behavior, and adhesion properties of cancer cells. It is therefore conceivable that interference with ERQC and/or ERAD can be used to selectively damage cancers. Indeed, inhibitors of the late stages of ERAD are already in the clinic against cancers such as multiple myeloma. Here, we review recent advances in our understanding of the complex relationship between glycoproteostasis and cancer biology and discuss the potential of ERQC and ERAD modulators for the selective targeting of cancer cell plasticity.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Tax

Lia

Santino

et al. 2019

Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…For enzyme-directing groups in our EDI catalog, we selected glycosidase-labile substrates for their general ability to pair with the Warburg effect in cancer cells, which favor glycolysis [ 13 , 14 ]. Specifically, we selected β-glucuronidase (β-glu) [ 15 ], α-mannosidase (α-man) [ 16 – 18 ], and β-galactosidase (β-gal) [ 19 , 20 ], because we envisioned that the established glycosidase expression and functional activity across many cancer types [ 21 , 22 ] would make these glycosidase-directed immunostimulants broadly applicable [ 23 , 24 ]. Among these glycosidases, β-glu is unique because it is localized intracellularly in healthy cells but found extracellularly in tumor and necrotic tissues, although it remains unclear whether extracellular β-glu is derived from cancer cells themselves or introduced through other sources such as tumor-infiltrating lymphocytes [ 3 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Comparing the immunogenicity of glycosidase-directed resiquimod prodrugs mediated by cancer cell metabolism

et al. 2020

View full text Add to dashboard Cite

We have recently developed an enzyme-directed immunostimulant (EDI) prodrug motif, which is metabolized to active immunostimulant by cancer cells and, following drug efflux, activates nearby immune cells, resulting in immunogenicity. In this study, we synthesized several EDI prodrugs featuring an imidazoquinoline immunostimulant resiquimod (a Toll-like receptor 7/8 agonist) covalently modified with glycosidase enzyme-directing groups selected from substrates of β-glucuronidase, α-mannosidase, or β-galactosidase. We compared the glycosidase-dependent immunogenicity elicited by each EDI in RAW-Blue macrophages following conversion to active immunostimulant by complementary glycosidase. At a cellular level, we examined EDI metabolism across three cancer cell lines (B16 melanoma, TC2 prostate, and 4T1 breast cancer). Comparing the relative immunogenicity elicited by each EDI/cancer cell combination, we found that B16 cells produced the highest EDI prodrug immunogenicity, achieving >95% of that elicited by unmodified resiquimod, followed by TC2 and 4T1 cells (40% and 30%, respectively). Immunogenicity elicited was comparable for a given cell type and independent of the glycosidase substrate in the EDIs or differences in functional glycosidase activity between cell lines. Measuring drug efflux of the immunostimulant payload and efflux protein expression revealed that EDI/cancer cell-mediated immunogenicity was governed by efflux potential of the cancer cells. We determined that, following EDI conversion, immunostimulant efflux occurred through both P-glycoprotein-dependent and P-glycoprotein-independent transport mechanisms. Overall, this study highlights the broad ability of EDIs to couple immunogenicity to the metabolism of many cancers that exhibit drug efflux and suggests that designing future generations of EDIs with immunostimulant payloads that are optimized for drug efflux could be particularly beneficial.

show abstract

“…During the formation of these N-linked polysaccharides (N-glycans), a chitobiose core is attached to suitable asparagines in the ER, which are then highly decorated with mannoses to generate high mannose N-glycans. Subsequently, these mannoses are often trimmed by mannosidases (MAN1B1 in the ER and MAN1A1, MAN1A2 and MAN1C1 in the Golgi apparatus), allowing a plethora of other glycosyl-transferases to generate complex and hybrid N-glycans [ 12 ]. Therefore, a common notion is that high mannose N-glycans are precluded from other glycan modifications.…”

Section: Introductionmentioning

confidence: 99%

High Mannose N-Glycans Promote Migration of Bone-Marrow-Derived Mesenchymal Stromal Cells

Alonso-Garcia

Chaboya

et al. 2020

IJMS

View full text Add to dashboard Cite

For hundreds of indications, mesenchymal stromal cells (MSCs) have not achieved the expected therapeutic efficacy due to an inability of the cells to reach target tissues. We show that inducing high mannose N-glycans either chemically, using the mannosidase I inhibitor Kifunensine, or genetically, using an shRNA to silence the expression of mannosidase I A1 (MAN1A1), strongly increases the motility of MSCs. We show that treatment of MSCs with Kifunensine increases cell migration toward bone fracture sites after percutaneous injection, and toward lungs after intravenous injection. Mechanistically, high mannose N-glycans reduce the contact area of cells with its substrate. Silencing MAN1A1 also makes cells softer, suggesting that an increase of high mannose N-glycoforms may change the physical properties of the cell membrane. To determine if treatment with Kifunensine is feasible for future clinical studies, we used mass spectrometry to analyze the N-glycan profile of MSCs over time and demonstrate that the effect of Kifunensine is both transitory and at the expense of specific N-glycoforms, including fucosylations. Finally, we also investigated the effect of Kifunensine on cell proliferation, differentiation, and the secretion profile of MSCs. Our results support the notion of inducing high mannose N-glycans in MSCs in order to enhance their migration potential.

show abstract

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Abstract: Our study demonstrates the prognostic role of MAN1A1 in breast cancer by affecting the adhesive properties of tumour cells and the strong influence of this glycosylation enzyme on the prognostic impact of some adhesion proteins.

Cited by 48 publications

References 22 publications

Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Comparing the immunogenicity of glycosidase-directed resiquimod prodrugs mediated by cancer cell metabolism

High Mannose N-Glycans Promote Migration of Bone-Marrow-Derived Mesenchymal Stromal Cells

Contact Info

Product

Resources

About