Abstract B38: Troglitazone enhances breast cancer cell 18F-FDG uptake and intracelluar lactic acid accumulation through PPAR-r independent activation of the MAPK pathway.

Abstract

Abstract Purpose: There is growing interest in the anti-tumor effects of thiazolidinediones including troglitazone (TGZ). In this study, we assessed how TGZ acts on cancer cell glucose uptake, and further investigated its mechanism and relation to cancer cell survival. Methods: T47D human breast cancer cells were treated with TGZ and measured for trypan blue and MTT assay-based cell viability, FDG uptake, intra- and extracellular lactic acid levels, and superoxide production. Involvement of signaling pathways for FDG uptake was investigated with specific kinase inhibitors and Western blots. Results: TGZ caused dose-dependent suppression of T47D cell survival, and glucose deprivation substantially enhanced the killing effect from 15.6% to 84.2% of cells. However, in contrast to energy restriction mimetic agents that reduced FDG uptake, TGZ stimulated a prompt increase of FDG uptake that reached 245.0% of controls by 10 μM at 1 h. This response was poorly replicated by rosiglitazone and was unaffected by GW9662, indicating a PPAR-independent mechanism of action. TGZ rapidly stimulated mitogen-activated protein kinase (MAPK) activity, and inhibition of this pathway with PD98059, as well as inhibition of epidermal growth factor receptor (EGFR) activity with BIBX1382, completely abrogated the ability of TGZ to enhance FDG uptake. The increase in glucose uptake was accompanied by elevated lactic acid accumulation in the cells but not culture media. This indicates that TGZ stimulates glycolytic activity but suppresses lactic acid extrusion, which may contribute to its anti-tumor effects. Conclusion: TGZ-induced suppression of T47D cell survival is potentiated by restricted glucose availability, but is uniquely accompanied by enhanced FDG uptake that occurs via PPAR-independent MAPK activation. This is associated with an increase in glycolytic metabolism along with suppression of lactic acid extrusion, which may play a role in the anti-tumor effect of TGZ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B38.