Nives Škorja (Author), Klemen Dolinar (Author), Katarina Miš (Author), Urška Matkovič (Author), Maruša Rajh (Author), Mojca Pavlin (Author), Matej Podbregar (Author), Sergej Pirkmajer (Author)

Abstract

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-1[alpha] (HIF-1[alpha]), 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.

Keywords

celice skeletnih mišic;rak;dikloroacetat;skeletal muscle cells;cancer;dichloroacetate;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL MF - Faculty of Medicine
UDC: 616-006
COBISS: 72730115 Link will open in a new window
ISSN: 1422-0067
Views: 89
Downloads: 33
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Other data

Secondary language: Slovenian
Secondary keywords: celice skeletnih mišic;rak;dikloroacetat;
Type (COBISS): Article
Pages: str. 1-24
Volume: ǂVol. ǂ22
Issue: ǂno. ǂ16
Chronology: 2021
DOI: 10.3390/ijms22168610
ID: 14889992