Aerobic glycolysis is commonly observed in
tumor cells, including
triple-negative breast cancer (TNBC) cells, and the rate of aerobic glycolysis is higher in TNBC cells than in non-TNBC cells.
Hexokinase 2 (HK2) is a key
enzyme in the glycolytic pathway and a target of the
transcription factor c-Myc, which is highly expressed in TNBC and promotes aerobic glycolysis by enhancing HK2 expression. As an inhibitor of HK2,
3-bromopyruvic acid (3-BrPA) exhibits good therapeutic efficacy in intrahepatic and extrahepatic
tumors and inhibits the proliferation of human
tumor cells with high expression levels of c-Myc in vivo and in vitro. In addition, 3-BrPA combines with
photodynamic therapy to inhibit TNBC cell migration.
Thioredoxin-interacting
protein (TXNIP) competes with c-Myc to reduce
glucose consumption in
tumor cells to restrain cell proliferation. A comparative analysis was performed in the present study in TNBC (HCC1143) and non-TNBC (MCF-7) cell lines to explore the effect of 3-BrPA on energy metabolism in TNBC cells and to investigate the possible mechanism of action. Cell viability and apoptosis were detected through Cell Counting Kit-8 and flow cytometry assays, respectively. Expression levels of HK2,
glucose transporter 1, TXNIP, c-Myc and mitochondria-regulated apoptosis pathway
proteins were measured through western blotting. 3-BrPA inhibited cell proliferation, downregulated c-Myc and HK2 expression, and upregulated TXNIP expression in TNBC cells, but it doesn't have the same effect on non-TNBC cells. Furthermore, 3-BrPA induced the typical manifestations of mitochondrial-mediated apoptosis such as decreasing Bcl-2 expression and increasing Bax, Cyt-C and
Caspase-3 expression. The present results suggested that 3-BrPA promoted TXNIP
protein expression and reduced HK2 expression in TNBC cells by downregulating c-Myc expression, inhibiting glycolysis including suppressing
lactate generation, intracellular
ATP generation and HK activity, inducing mitochondrial-mediated apoptosis and eventually suppressing TNBC cell proliferation. These findings may reveal a novel therapeutic target for the clinical treatment of TNBC.