Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

Rhys G Morgan; Elek Molnar; Rosie F Jones; Tracey J Collard; Jon D Lane; Alexander Greenhough; Christos Paraskeva; Ann C Williams

doi:10.1038/bjc.2015.4

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

Rhys G Morgan
, Elek Molnar
, Rosie F Jones
, Tracey J Collard
, Jon D Lane
, Alexander Greenhough
, Christos Paraskeva
, Ann C Williams

Research output: Contribution to journal › Article (Academic Journal) › peer-review

16 Citations (Scopus)

424 Downloads (Pure)

Abstract

Background:

LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein.

Methods:

Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5.

Results:

Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network.

Conclusions:

Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function.

Original language	English
Pages (from-to)	714-719
Number of pages	6
Journal	British Journal of Cancer
Volume	112
Issue number	4
Early online date	22 Jan 2015
DOIs	https://doi.org/10.1038/bjc.2015.4
Publication status	Published - 17 Feb 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

LGR5
glycosylation
colorectal cancer
stem cell
nutrient stress
microenvironment

Access to Document

10.1038/bjc.2015.4

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Final published version, 1.28 MBLicence: CC BY-NC-SA

Handle.net

Persistent link

Development of biotin-tagged affinity ligands and fluorophore-conjugated probes for the study of native kainate receptors
Molnar, E. (Principal Investigator)
1/03/13 → 1/03/16
Project: Research

Wolfson Bioimaging Facility
Jepson, M. (Manager)
Facility/equipment: Facility

Professor Jon D Lane
- Jon.Lanebristol.acuk
- School of Biochemistry and Biomedical Sciences - Professor of Cell Biology
- Cancer
- Dynamic Cell Biology
Person: Academic , Member
Professor Elek Molnar
- Elek.Molnarbristol.acuk
- School of Psychology and Neuroscience - Professor
- Health and Life Sciences - Academic Director (International Education)
- Bristol Neuroscience
Person: Academic , Member

Cite this

Morgan, R. G., Molnar, E., Jones, R. F., Collard, T. J., Lane, J. D., Greenhough, A., Paraskeva, C., & Williams, A. C. (2015). Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells. British Journal of Cancer, 112(4), 714-719. https://doi.org/10.1038/bjc.2015.4

@article{7181b36364ce4ca0803e4b489684718e,

title = "Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells",

abstract = "Background: LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein. Methods: Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5. Results: Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network. Conclusions: Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function.",

keywords = "LGR5, glycosylation, colorectal cancer, stem cell, nutrient stress, microenvironment",

author = "Morgan, \{Rhys G\} and Elek Molnar and Jones, \{Rosie F\} and Collard, \{Tracey J\} and Lane, \{Jon D\} and Alexander Greenhough and Christos Paraskeva and Williams, \{Ann C\}",

year = "2015",

month = feb,

day = "17",

doi = "10.1038/bjc.2015.4",

language = "English",

volume = "112",

pages = "714--719",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "4",

}

Morgan, RG, Molnar, E, Jones, RF, Collard, TJ, Lane, JD , Greenhough, A, Paraskeva, C & Williams, AC 2015, 'Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells', British Journal of Cancer, vol. 112, no. 4, pp. 714-719. https://doi.org/10.1038/bjc.2015.4

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells. / Morgan, Rhys G; Molnar, Elek; Jones, Rosie F et al.
In: British Journal of Cancer, Vol. 112, No. 4, 17.02.2015, p. 714-719.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells

T2 - implications for targeting cancer stem cells

AU - Morgan, Rhys G

AU - Molnar, Elek

AU - Jones, Rosie F

AU - Collard, Tracey J

AU - Lane, Jon D

AU - Greenhough, Alexander

AU - Paraskeva, Christos

AU - Williams, Ann C

PY - 2015/2/17

Y1 - 2015/2/17

N2 - Background: LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein. Methods: Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5. Results: Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network. Conclusions: Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function.

AB - Background: LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein. Methods: Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5. Results: Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network. Conclusions: Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function.

KW - LGR5

KW - glycosylation

KW - colorectal cancer

KW - stem cell

KW - nutrient stress

KW - microenvironment

U2 - 10.1038/bjc.2015.4

DO - 10.1038/bjc.2015.4

M3 - Article (Academic Journal)

C2 - 25611300

SN - 0007-0920

VL - 112

SP - 714

EP - 719

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

Abstract

UN SDGs

Keywords

Access to Document

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Projects

Development of biotin-tagged affinity ligands and fluorophore-conjugated probes for the study of native kainate receptors

Equipment

Wolfson Bioimaging Facility

Profiles

Professor Jon D Lane

Professor Elek Molnar

Cite this