20.500.12556/RUL-135749 Suppression of pyruvate dehydrogenase kinase by dichloroacetate in cancer and skeletal muscle cells is isoform specific and partially independent of HIF-1α Inhibition of pyruvate dehydrogenase kinase (PDK) emerged as a potential strategy for treatment of cancer and metabolic disorders. Dichloroacetate (DCA), a prototypical PDK inhibitor, reduces the abundance of some PDK isoenzymes. However, the underlying mechanisms are not fully characterized and may differ across cell types. We determined that DCA reduced the abundance of PDK1 in breast (MDA-MB-231) and prostate (PC-3) cancer cells, while it suppressed both PDK1 and PDK2 in skeletal muscle cells (L6 myotubes). The DCA-induced PDK1 suppression was partially dependent on hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator of PDK1, in cancer cells but not in L6 myotubes. However, the DCA-induced alterations in the mRNA and the protein levels of PDK1 and/or PDK2 did not always occur in parallel, implicating a role for post-transcriptional mechanisms. DCA did not inhibit the mTOR signaling, while inhibitors of the proteasome or gene silencing of mitochondrial proteases CLPP and AFG3L2 did not prevent the DCA-induced reduction of the PDK1 protein levels. Collectively, our results suggest that DCA reduces the abundance of PDK in an isoform-dependent manner via transcriptional and post-transcriptional mechanisms. Differential response of PDK isoenzymes to DCA might be important for its pharmacological effects in different types of cells. skeletal muscle cells cancer dichloroacetate pyruvate dehydrogenase kinase pyruvate dehydrogenase complex myotubes celice skeletnih mišic rak dikloroacetat true false true Angleški jezik Slovenski jezik Članek v reviji 2022-03-30 12:11:05 2022-03-30 12:11:08 2022-09-14 04:14:58 0000-00-00 00:00:00 2021 0 0 26 str. iss. 16, art. 8610 Vol. 22 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-006 1422-0067 10.3390/ijms22168610 72730115 RAZ_Skorja_Nives_2021.pdf RAZ_Skorja_Nives_2021.pdf 1 D034B16D3CE2290F867FFA6B2CAA7228 955c649f5c5686d44865a45464603becd677b288ec2c9b1fde7d80ba097434ca fc522030-b011-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155022 https://www.mdpi.com/1422-0067/22/16/8610 1 b34dfd04-b011-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155021 Medicinska fakulteta Fakulteta za elektrotehniko Fakulteta za farmacijo 0 0 0