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

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J Clin Invest_124(1)_367-384.pdf6.4 MBPDFView/Open
Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/54686

Title: Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways
Authors: Onodera, Yasuhito Browse this author →KAKEN DB
Nam, Jin-Min Browse this author
Bissell, Mina J. Browse this author
Issue Date: 2-Jan-2014
Publisher: Amer soc clinical investigation inc
Journal Title: Journal of clinical investigation
Volume: 124
Issue: 1
Start Page: 367
End Page: 384
Publisher DOI: 10.1172/JCI63146
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, beta 1 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-l alpha/2 alpha, 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.
Type: article
URI: http://hdl.handle.net/2115/54686
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 小野寺 康仁

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