Troglitazone exerts metabolic and antitumor effects on T47D breast cancer cells by suppressing mitochondrial pyruvate availability

Abstract

The aim of the present study was to investigate the metabolic and anticancer effects of troglitazone (TGZ) with a focus on the potential role of mitochondrial pyruvate utilization. 2-Deoxyglucose (2-DG) was more cytotoxic in CT26 cancer cells compared with T47D cells, despite a smaller suppression of glucose uptake. On the other hand, TGZ caused a more prominent shift to glycolytic metabolism and was more cytotoxic in T47D cells. Both effects of TGZ on T47D cells were dose-dependently reversed by addition of methyl pyruvate (mPyr), indicating suppression of mitochondrial pyruvate availability. Furthermore, UK5099, a specific mitochondrial pyruvate carrier inhibitor, closely simulated the metabolic and antitumor effects of TGZ and their reversal by mPyr. This was accompanied by a substantial reduction of activated p70S6K. In CT26 cells, UK5099 did not reduce activated p70S6K and only modestly decreased cell proliferation. In these cells, combining glutamine restriction with UK5099 further increased glucose uptake and completely suppressed cell proliferation. Thus, TGZ-mediated inhibition of mitochondrial pyruvate utilization is an effective treatment for cancer cells that are more dependent on mitochondrial glucose metabolism. By contrast, cancer cells that are more glycolysis-dependent may require suppression of glutamine utilization in addition to blocking mitochondrial pyruvate availability for a full antitumor effect.

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