Upregulation of glucose-dependent metabolism, called aerobic glycolysis, is a feature of many tumours, especially those that are aggressive or at an advanced stage. Glycolysis provides the ATP to supply the tumour cell's high bioenergetic needs and, if there are excess metabolites, also provides the precursors for the synthesis of lipids that are required for membrane production and post-translational modification of proteins. In Cancer Cell, Craig Thompson and colleagues report that inhibition of a key enzyme linking glucose metabolism to lipid synthesis suppresses tumour growth.

Aerobic glycolysis produces pyruvate, which enters a tricarboxylic acid cycle in the mitochondria to produce citrate, which is in turn exported to the cytosol. Citrate is cleaved by ATP citrate lyase (ACLY) to produce acetyl-CoA, which is the main building block for lipids in the cell. The authors therefore assessed the effects of ACLY inhibition by short interfering RNA (siRNA) knockdown on tumour cells. Treatment of the human lung adenocarcinoma cell line A549 with anti-ACLY siRNA led to reduced levels of ACLY and acetyl-CoA, and a reduction in glucose-dependent lipid synthesis. By 72-hours post-treatment, cells had accumulated in the G1 phase of the cell cycle, resulting in a 30% decrease in cell numbers. A549 clones with either stable siRNA knockdown of ACLY or with vector-only transfection were injected into opposite flanks of nude mice to compare tumorigenicity. ACLY knockdown cells formed smaller, more differentiated tumours than the controls, marked by glandular structures that secreted mucin. The increased differentiation was a surprising finding, so the authors confirmed this effect with a well-known model of tumour cell differentiation, the human chronic myelogenous leukaemia cell line, K562; ACLY knockdown also caused erythroid differentiation in these cells.

Thompson and colleagues also examined the effect of an ACLY chemical inhibitor SB204990 on tumour cell growth. Having shown that SB204990 reduced lipid synthesis and caused G1 arrest in a highly glycolytic normal cell line, they went on to test it on three human tumour cell lines — two with high rates of glycolysis (A549 and PC3) were sensitive to SB204990, whereas one with a low rate of glycolysis (SKOV3) was more resistant. When mice bearing xenografts using these cell lines were treated with SB204990, a cytostatic effect as well as differentiation into glandular mucin-expressing structures was evident in A549 and PC3 xenografts but not SKOV3 xenografts.

The failure of ACLY inhibition to suppress the growth of tumours that do not have high rates of glycolysis indicates that there are alternative lipogenic pathways that tumour cells can use. However, ACLY inhibitors — as well as statins, farnesyl transferase inhibitors and fatty acid synthesis inhibitors — might be useful in combination with other agents to treat advanced tumours, which often have high rates of glycolysis.