The authors declare no conflict of interest.
Original Research Article
Wnt/β-catenin signaling pathway and thioredoxin-interacting protein (TXNIP) mediate the “glucose sensor” mechanism in metastatic breast cancer-derived cells MDA-MB-231†
Version of Record online: 23 NOV 2011
Copyright © 2011 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 227, Issue 2, pages 578–586, February 2012
How to Cite
Vaira, S., Friday, E., Scott, K., Conrad, S. and Turturro, F. (2012), Wnt/β-catenin signaling pathway and thioredoxin-interacting protein (TXNIP) mediate the “glucose sensor” mechanism in metastatic breast cancer-derived cells MDA-MB-231. J. Cell. Physiol., 227: 578–586. doi: 10.1002/jcp.22757
- Issue online: 23 NOV 2011
- Version of Record online: 23 NOV 2011
- Accepted manuscript online: 29 MAR 2011 08:56AM EST
- Manuscript Accepted: 17 MAR 2011
- Manuscript Received: 16 DEC 2010
- Board of Regents, Louisiana
In this study we investigated the effect of glucose on GSK3β and β-catenin expression and the involvement of the N-linked glycosylation and hexosamine pathways in the Wnt canonical pathway in response to in vitro conditions resembling normoglycemia (5 mmol) and hyperglycemia (20 mmol) in the metastatic breast cancer-derived cell line MDA-MB-231. We also investigated the relationship between this circuitry and the thioredoxin-interacting protein (TXNIP) regulation that seems to be related. MDA-MB-231 cells were grown either in 5 or 20 mM glucose chronically prior to plating. For glucose shift (5/20), cells were plated in 5 mM glucose and shifted to 20 mM at time 0. Both protein and mRNA levels for GSK3β but only the protein expression for β-catenin, were increased in response to high glucose. Furthermore, we assessed the response of GSK3β, β-catenin, and TXNIP to inhibition of the N-linked glycosylation, hexosamine, and Wnt pathways. Wnt signaling pathway activation was validated by specific reporter assay. We show that high levels of glucose regulate mRNA and protein expression of GSK3β, and consequently higher levels of activated β-catenin protein, which locates to the nucleus and is associated with increased levels of cyclin D1 expression. This event coincides with increased level of N-terminal Ser 9 phosphorylation of GSK3β protein. The inhibition of both the hexosamine pathway and N-linked glycosylation along with Wnt signaling pathway by sFRP1 and DKK1 is associated with significant decrease of the protein levels of GSK3β, β-catenin, and TXNIP RNA. Our work illuminates a novel and never described before function of this signaling pathway that relates glucose metabolism with redox regulation mechanism. J. Cell. Physiol. 227: 578–586, 2012. © 2011 Wiley Periodicals, Inc.