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Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2014 Jan; Vol. 124 (1), pp. 367-84. Date of Electronic Publication: 2013 Dec 09. - Publication Year :
- 2014
-
Abstract
- There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between "normal" and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.
- Subjects :
- Adenylyl Cyclases metabolism
Biosynthetic Pathways
Breast Neoplasms metabolism
Breast Neoplasms mortality
Carrier Proteins metabolism
Cell Line
ErbB Receptors metabolism
Female
Glucose metabolism
Glucose Transporter Type 3 metabolism
Glycosylation
Humans
Integrin beta1 metabolism
MAP Kinase Kinase Kinases metabolism
Membrane Proteins metabolism
Oncogenes
Oxygen Consumption
Phenotype
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt metabolism
Second Messenger Systems
Shelterin Complex
Thyroid Hormones metabolism
Up-Regulation
Thyroid Hormone-Binding Proteins
Acetylglucosamine metabolism
Cell Transformation, Neoplastic metabolism
Glycolysis
Guanine Nucleotide Exchange Factors metabolism
Telomere-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 124
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 24316969
- Full Text :
- https://doi.org/10.1172/JCI63146