Abstract
Most cancer cells depend on enhanced glucose and glutamine (Gln) metabolism for growth and survival. Oncogenic metabolism provides biosynthetic precursors for nucleotides, lipids, and amino acids; however, its specific roles in tumor progression are largely unknown. We previously showed that distal-less homeobox-2 (Dlx-2), a homeodomain transcription factor involved in embryonic and tumor development, induces glycolytic switch and epithelial-mesenchymal transition (EMT) by inducing Snail expression. Here we show that Dlx-2 also induces the expression of the crucial Gln metabolism enzyme glutaminase (GLS1), which converts Gln to glutamate. TGF-β and Wnt induced GLS1 expression in a Dlx-2-dependent manner. GLS1 shRNA (shGLS1) suppressed in vivo tumor metastasis and growth. Inhibition of Gln metabolism by shGLS1, Gln deprivation, and Gln metabolism inhibitors (DON, 968 and BPTES) prevented Dlx-2-, TGF-β-, Wnt-, and Snail-induced EMT and glycolytic switch. Finally, shDlx-2 and Gln metabolism inhibition decreased Snail mRNA levels through p53-dependent upregulation of Snail-targeting microRNAs. These results demonstrate that the Dlx-2/GLS1/Gln metabolism axis is an important regulator of TGF-β/Wnt-induced, Snail-dependent EMT, metastasis, and glycolytic switch.
Highlights
Metabolic changes in cancer cells support higher rates of cell proliferation and growth compared to normal cells [1,2,3,4,5,6,7,8]
distal-less homeobox-2 (Dlx-2) mRNA levels in the different cell lines were as follows relative to levels in HCT116 cells, which were used as a reference cell line: 0.446-fold in MCF-7, 0.351-fold in MDA-MB231, 0.322-fold in A549, 1.389fold in HepG2, and 1.144-fold in HeLa
These enzymes are involved in Gln metabolism, glycolysis, pentose phosphate pathway (PPP), and fatty acid/cholesterol synthesis, respectively, suggesting that Dlx-2 may activate several oncogenic metabolic pathways
Summary
Metabolic changes in cancer cells support higher rates of cell proliferation and growth compared to normal cells [1,2,3,4,5,6,7,8]. Most cancer cells rely on glycolysis more than mitochondrial oxidative phosphorylation for ATP production, even in the presence of oxygen; as a consequence, they exhibit increased glucose (Glc) uptake and lactate (Lac) production [1,2,3]. This phenomenon, termed the “Warburg effect” or glycolytic switch, is thought to increase the availability of biosynthetic precursors for nucleotides, lipids, and amino acids required for cancer cell proliferation. Gln anaplerosis is crucial in maintaining cancer cell growth and development. GLS1 shRNA (shGLS1), and the GLS-specific inhibitors bis-2(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and 968, reduce the growth of several cancer types in xenograft models [10, 14, 17]
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