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Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways
Yasuhito Onodera, … , Jin-Min Nam, Mina J. Bissell
Yasuhito Onodera, … , Jin-Min Nam, Mina J. Bissell
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):367-384. https://doi.org/10.1172/JCI63146.
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Research Article Oncology

Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways

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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.

Authors

Yasuhito Onodera, Jin-Min Nam, Mina J. Bissell

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Figure 3

Glucose uptake and metabolism determine the signaling activity and morphology of malignant and nonmalignant mammary epithelial cells.

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Glucose uptake and metabolism determine the signaling activity and morph...
(A–D) T4-2 cells were transfected with control or GLUT3 siRNA and cultured in 3D-OT lrECM with the indicated glucose concentrations. (A) Confocal IF images. Green, α6 integrin; red, nuclei. Scale bars: 20 μm. (B) Cell number at the colony midsection. (C) Percent colonies with basal polarity. (D) Western blot of signaling intermediates and GLUT3. (E–H) S1 cells were infected with empty or GLUT3-HA–encoding lentivirus and cultured in 3D lrECM with 4 mM 2DG and/or the indicated glucose concentrations. (E) Confocal IF images. Green, α6 integrin; red, nuclei. Immunostaining with anti-HA antibody is also shown. Scale bars: 20 μm. (F) Cell number at the colony midsection. (G) Percent colonies with basal polarity. (H) Western blot of signaling intermediates, GLUT3, and HA epitope. Asterisks denote nonspecific bands. In B, C, F, and G, data are mean ± SD of triplicate experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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