Fig. 5.

Proposed model of the mechanisms of TPD54 in regulation of PDH E1α in breast cancer cells and its effect on metformin response. TPD54 interacts with pyruvate dehydrogenase complex and affects PDH protein and enzyme activity. Loss of TPD54 causes increased phosphorylation of PDH E1α at S232 by PDK1, resulting in further ubiquitination and protein degradation of PDH E1α, and this phenotype can be restored by PDK1 knockdown (b, c). Loss of TPD54 leads to reduced oxidative phosphorylation and ROS production, which contribute to reduced metformin cytotoxicity (a, b). This can be reversed by activating pyruvate dehydrogenase by knocking down upstream inhibitory kinases PDK2 (b, c)