The novel function of tumor protein D54 in regulating pyruvate dehydrogenase and metformin cytotoxicity in breast cancer.

摘要: The role of tumor protein D54 in breast cancer has not been studied and its function remains unclear. In our previous pharmacogenomic studies using lymphoblastoid cell line (LCL), this identified to affect metformin response. Although widely as a prophylactic chemotherapeutic drug, there is still lack biomarkers predicting the response cancer. study, we revealed novel TPD54 through understanding how altered sensitivity metformin. altering cellular treatment was carried out by either knockdown or overexpression TPD54, followed measuring viability reactive oxygen species (ROS) production MCF7 patient-derived xenografts. Functional analysis cells demonstrated studying localization identification potential binding partners immunoprecipitation mass spectrometry. effect on pyruvate dehydrogenase (PDH) regulation western blot, immunoprecipitation, site-directed mutagenesis. inhibited colony formation enhanced Mechanistic study indicated that had mitochondrial localization, bound stabilized E1α blocking kinase 1 (PDK1)-mediated serine 232 phosphorylation. increased PDH degradation led decreased enzyme activity, which reduced consumption production, thus contributing resistance treatment. We have discovered mechanism regulates affects Our findings highlight important post-translational PDK1 application biomarker for selecting tumors may be sensitive therapy. These provide new insights into complexes mechanisms