BRCA1 overexpression attenuates breast cancer cell growth and migration by regulating the pyruvate kinase M2-mediated Warburg effect via the PI3K/AKT signaling pathway

Abstract

This work explored the mechanism of the effect of breast-cancer susceptibility gene 1 (BRCA1) on the metabolic characteristics of breast cancer cells, including the Warburg effect and its specific signaling. We transfected MCF-7 cells with a BRCA1-encoding LXSN plasmid or PKM2 siRNA and examined cancer cell metabolism using annexin V staining, inhibitory concentration determination, Western blotting, glucose uptake and lactic acid content measurements, and Transwell assays to assess glycolytic activity, cell apoptosis, and migration, and sensitivity to anti-cancer treatment. The BRCA1-expressing MCF-7 cells demonstrated low PKM2 expression and decreased glycolytic activity (downregulated hexokinase 2 (HK2) expression, upregulated isocitrate dehydrogenase 1 (IDH1) expression, and reduced O2 and glucose consumption and lactate production) via regulation of PI3K/AKT pathway compared with the empty LXSN group. BRCA1 transfection slightly increased apoptotic activity, decreased cell migration, and increased the IC50 index for doxorubicin, paclitaxel, and cisplatin. Inhibiting PKM2 using siRNA attenuated the IC50 index for doxorubicin, paclitaxel, and cisplatin compared with the control. Inhibiting PKM2 activated PI3K/AKT signaling, increased apoptosis, and decreased MCF-7 cell migration. Our data suggest that BRCA1 overexpression reverses the Warburg effect, inhibits cancer cell growth and migration, and enhances the sensitivity to anti-cancer treatment by decreasing PKM2 expression regulated by PI3K/AKT signaling. These novel metabolic findings represent a potential mechanism by which BRCA1 exerts its inhibitory effect on breast cancer.