title: MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells.
abstract: Aerobic glycolysis in cancer cells is regulated by multiple effectors that include Akt and pyruvate kinase M2 (PKM2). Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed by human breast and other carcinomas. Here we show that transformation of rat fibroblasts by the oncogenic MUC1-C subunit is associated with Akt-mediated increases in glucose uptake and lactate production, consistent with the stimulation of glycolysis. The results also demonstrate that the MUC1-C cytoplasmic domain binds directly to PKM2 at the B- and C-domains. Interaction between the MUC1-C cytoplasmic domain Cys-3 and the PKM2 C-domain Cys-474 was found to stimulate PKM2 activity. Conversely, epidermal growth factor receptor (EGFR)-mediated phosphorylation of the MUC1-C cytoplasmic domain on Tyr-46 conferred binding to PKM2 Lys-433 and inhibited PKM2 activity. In human breast cancer cells, silencing MUC1-C was associated with decreases in glucose uptake and lactate production, confirming involvement of MUC1-C in the regulation of glycolysis. In addition, EGFR-mediated phosphorylation of MUC1-C in breast cancer cells was associated with decreases in PKM2 activity. These findings indicate that the MUC1-C subunit regulates glycolysis and that this response is conferred in part by PKM2. Thus, the overexpression of MUC1-C oncoprotein in diverse human carcinomas could be of importance to the Warburg effect of aerobic glycolysis.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michio
authors.initials: M
authors.lastname: Kosugi
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000332:Aerobiosis; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D020868:Gene Silencing; D006019:Glycolysis; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000378:metabolism*; D051381:Rats
chemical_list: D018396:Mucin-1; D050505:Mutant Proteins; D021122:Protein Subunits; D019000:Phosphotyrosine; D011770:Pyruvate Kinase; D066246:ErbB Receptors; D003545:Cysteine