Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Abstract

ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

“…In addition, as we showed previously for RAS-and PDGF receptordriven transformation (6), HSF1 is also important for HER2-driven transformation (9). HER2 or its ligand heregulin β1 also enhance the efficiency of transformation by increasing levels of HSF1 itself (16,29). Consistent with HER2 increasing HSF1 levels, we observed that 88.4% of HER2-positive invasive tumors were HSF1-positive and 40.7% had high levels of HSF1, the greatest percentage of any molecular subtype.…”

“…Evidence for mechanistic interplay between HSF1 and HER2 has recently begun to emerge. HER2 and HSF1 work together to influence cancer metabolism by driving lactate dehydrogenase A (LDH-A) expression and shifting tumor cells into a glycolytic state (29). In addition, as we showed previously for RAS-and PDGF receptordriven transformation (6), HSF1 is also important for HER2-driven transformation (9).…”

MicroRNA-125b Confers the Resistance of Breast Cancer Cells to Paclitaxel through Suppression of Pro-apoptotic Bcl-2 Antagonist Killer 1 (Bak1) Expression

“…Twenty-four hours later, the medium was replaced with fresh medium with or without Taxol and incubated for 48 h. Cell viability was determined using CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega) as previously reported (21).…”

Emerging functional roles of nuclear receptors in breast cancer

“…Overexpression of mitochondrial ERBB2 decreases mitochondrial electron transport chain activity and enhances cellular glycolysis (Ding et al 2012). In addition, ERBB2 influences the glycolytic phenotype through upregulation of lactate dehydrogenase (Zhao et al 2009) as well as REV-ERBA, an NR that was reported to be involved in glycolysis and fatty acid synthesis in breast cancer cells (Kourtidis et al 2010). In summary, the ERRs are prominent regulators of gene networks controlling glycolysis and oxidative phosphorylation in metabolic tissues.…”