Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing

Abstract

Targeting glycolysis for cancer treatment has been investigated as a therapeutic method but has not offered a feasible chemotherapeutic strategy. Our aim was to examine whether AMP-activated protein kinase (AMPK), a conditional oncogene, rescues the energetic stress and cytotoxicity induced by 2-deoxyglucose (2-DG), a glycolytic inhibitor, and the related mechanisms. Luciferin/luciferase adenosine triphosphate (ATP) determination, Western analysis, qRT-PCR analyses, MTT growth assay, clonogenic assay, and statistical analysis were performed in this study. 2-DG decreased ATP levels and subsequently activated AMPK, which contribute to intracellular ATP recovery in MCF-7 cells thus exhibiting no apparent cytotoxicity. Compound C, an AMPK inhibitor, further potentiates 2-DG-induced decrease in ATP levels and inhibits their recovery. 2-DG, via AMPK activation, stimulated cAMP response element-binding protein (CREB) phosphorylation and activity and promoted nuclear peroxisome proliferator-activated receptor gamma coactivator-1-beta (PGC-1β) and estrogen-related receptor α (ERRα) protein expression, leading to augmented mitochondrial biogenesis and expression of fatty acid oxidation (FAO) genes including PPARα, MCAD, CPT1C, and ACO. This metabolic adaptation elicited by AMPK counteracts the ATP-depleting and cancer cell-killing effect of 2-DG. However, 2-DG in combination with AMPK antagonists or small interfering RNA caused a dramatic increase in cytotoxicity in MCF-7 but not in MCF-10A cells. Similarly, when combined with inhibition of CREB/PGC-1β/ERRα pathway, 2-DG saliently suppressed mitochondrial biogenesis and the expression of FAO genes, depleted ATP production, and enhanced cytotoxicity in cancer cells. Collectively, the combination of 2-DG and AMPK inhibition synergistically enhanced the cytotoxic potential in breast cancer cells with a relative nontoxicity to normal cells and may offer a promising, safe, and effective breast cancer therapeutic strategy.

Cytotoxic activity of physodic acid and acetone extract fromHypogymnia physodesagainst breast cancer cell lines

“…According to a recent study, a broad spectrum of mechanisms may be responsible for the resistance of MCF-10A cells to anticancer compounds. These include differences in the subcellular localization of Bik (Trejo-Vargas et al 2015) and the KLF8/EGFR signalling pathway (Li et al 2015), differences in stearoyl-CoA desaturase-1 activity (Belkaid et al 2015) and combined inhibition by glycolysis and AMP-activated protein kinase (Wu et al 2015), and differences in mitochodrial-mediated apoptosis (Taha et al 2015). Therefore, the exact mechanism responsible for the selective activity of physodic acid in breast cancer should be further investigated.…”

Carnitine palmitoyltransferase 1C: From cognition to cancer

“…A recent study also indicates that CPT1C might be induced by the indirect action of activated AMPK in the MCF-7 breast cancer cell line [127]. This study showed that 2-deoxyglucose (2-DG), a glycolytic inhibitor, decreased ATP levels, Although AMPK emerges as the major contributor to the increase in CPT1C expression in cancer cells, other less explored mechanisms, such as epigenetic alterations by changes in DNA methylation, cannot be disregarded [128].…”

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

“…The activation of AMPK by solamargine has never been shown in the past. Activation of AMPK were reported to be involved in the anti-tumor responses in several cancer types including prostate, suggesting the tumor suppressor role of this kinase1617183940 although conflicting observations have also been shown1920. Nevertheless, our results suggested that activation of AMPK signaling was involved in effect of solamargine in the controlling the growth of CRPC cells.…”

“…AMPK signaling also involves in growth, differentiation and progression of cancer, and has emerged as an attractive therapetic target to various types of cancer161718. However, conflicting reports about its cellular functions in cancer have been reported.…”