title: Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.
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
authors: Y
authors: Onodera
authors: Jin-Min
authors: JM
authors: Nam
authors: Mina J
authors: MJ
authors: Bissell
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D053898:Biosynthetic Pathways; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006019:Glycolysis; D006031:Glycosylation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009857:Oncogenes; D010101:Oxygen Consumption; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015290:Second Messenger Systems; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D015854:Up-Regulation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000117:Acetylglucosamine; D000262:Adenylyl Cyclases; D002352:Carrier Proteins; D066246:ErbB Receptors; D005947:Glucose; D051274:Glucose Transporter Type 3; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D051057:Proto-Oncogene Proteins c-akt; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C116122:RAPGEF3 protein, human; C495687:SLC2A3 protein, human; C440809:TERF2IP protein, human; C512478:EGFR protein, human