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.
Highlights
Cancer cells are distinguished from their normal counterparts by metabolic differences that include increased utilization of glucose by aerobic glycolysis
We found that Mucin 1 (MUC1)-CD-induced transformation of 3Y1 cells is associated with an increase in glucose uptake (Fig. 1B) and lactate production (Fig. 1C), consistent with the stimulation of glycolysis
There was a significant increase in pyruvate kinase M2 (PKM2) activity in the MUC1-C cytoplasmic domain (MUC1-CD) transformed 3Y1 fibroblasts (Fig. 1D). 3Y1/vector cells express PKM2, but not PKM1, and MUC1-CDinduced transformation had no apparent effect on PKM2 levels (Fig. 1E)
Summary
Cancer cells are distinguished from their normal counterparts by metabolic differences that include increased utilization of glucose by aerobic glycolysis. The distinct region of PKM2, as compared to PKM1, functions in the allosteric activation of the enzyme by fructose-1,6-bisphosphate (FBP) [7] and its inactivation by phosphotyrosine containing proteins [8,9] Under these circumstances, the regulation of PKM2 activity dictates the metabolism of glucose to pyruvate, which is converted by lactate dehydrogenase (LDH) to lactate or is utilized by the mitochondrial tricarboxylic acid (TCA) cycle [10]. The regulation of PKM2 activity dictates the metabolism of glucose to pyruvate, which is converted by lactate dehydrogenase (LDH) to lactate or is utilized by the mitochondrial tricarboxylic acid (TCA) cycle [10] These findings have supported the need to more fully understand the signals that regulate aerobic glycolysis and PKM2 activity in malignant cells
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