Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules

Sirin A I Adham, Hasina Al Rawahi, Sumaya Habib, Mansour S. Al Moundhri, Alicia Viloria-Petit, Brenda L. Coomber

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Breast cancer (BC) arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM) adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively). Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX) treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants) compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/ hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.

Original languageEnglish
Article number0113103
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 17 2014

Fingerprint

hyperglycemia
Hyperglycemia
breast neoplasms
Breast Neoplasms
Molecules
Integrins
hypoglycemia
Proteins
Neuropilin-1
cells
Glycosylation
Hypoglycemia
Catenins
Vascular Endothelial Growth Factor Receptor
integrins
Cadherins
Medical problems
Vascular Endothelial Growth Factor A
Restoration
Tumors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules. / Adham, Sirin A I; Al Rawahi, Hasina; Habib, Sumaya; Al Moundhri, Mansour S.; Viloria-Petit, Alicia; Coomber, Brenda L.

In: PLoS One, Vol. 9, No. 11, 0113103, 17.11.2014.

Research output: Contribution to journalArticle

Adham, Sirin A I ; Al Rawahi, Hasina ; Habib, Sumaya ; Al Moundhri, Mansour S. ; Viloria-Petit, Alicia ; Coomber, Brenda L. / Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules. In: PLoS One. 2014 ; Vol. 9, No. 11.
@article{922b893bc38543e7aeeca932f6d5636b,
title = "Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules",
abstract = "Breast cancer (BC) arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM) adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively). Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX) treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants) compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/ hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.",
author = "Adham, {Sirin A I} and {Al Rawahi}, Hasina and Sumaya Habib and {Al Moundhri}, {Mansour S.} and Alicia Viloria-Petit and Coomber, {Brenda L.}",
year = "2014",
month = "11",
day = "17",
doi = "10.1371/journal.pone.0113103",
language = "English",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules

AU - Adham, Sirin A I

AU - Al Rawahi, Hasina

AU - Habib, Sumaya

AU - Al Moundhri, Mansour S.

AU - Viloria-Petit, Alicia

AU - Coomber, Brenda L.

PY - 2014/11/17

Y1 - 2014/11/17

N2 - Breast cancer (BC) arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM) adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively). Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX) treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants) compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/ hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.

AB - Breast cancer (BC) arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM) adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively). Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX) treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants) compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/ hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.

UR - http://www.scopus.com/inward/record.url?scp=84913580076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84913580076&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0113103

DO - 10.1371/journal.pone.0113103

M3 - Article

C2 - 25401697

AN - SCOPUS:84913580076

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - 0113103

ER -