Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4

摘要: Adenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction living cells. An isoform of this enzyme, adenylate 4 (AK4), localized mitochondrial matrix and believed to be involved stress, drug resistance, malignant transformation cancer, ATP regulation. However, molecular basis for AK4 functions remained determined. HeLa cells were transiently transfected with an small interfering RNA (siRNA), short hairpin (shRNA) plasmid, control shRNA expression vector, vector examine effect on cell proliferation, sensitivity anti-cancer drug, metabolome, gene expression, activity. knockdown treated increased production showed greater hypoxia cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting into nude mice revealed that grafted exhibited both slower proliferation reduced tumor sizes response CDDP. oxygen consumption rate FCCP treatment, while overexpression lowered it. Metabolome analysis levels tricarboxylic acid cycle intermediates, fumarate malate cells, them. Electron microscopy detected numbers Microarray two enzymes TCA cycle, succinate dehydrogenase A (SDHA) oxoglutarate dehydrogenease L (OGDHL), which are components SDH complex OGDH complex, supporting metabolomic results. We found was tolerance, resistance anti-tumor regulation These findings provide new potential target efficient anticancer therapies by controlling expression.