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

Povzetek

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.

Ključne besede

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

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL MF - Medicinska fakulteta
UDK: 616-006
COBISS: 72730115 Povezava se bo odprla v novem oknu
ISSN: 1422-0067
Št. ogledov: 89
Št. prenosov: 33
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: celice skeletnih mišic;rak;dikloroacetat;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-24
Letnik: ǂVol. ǂ22
Zvezek: ǂno. ǂ16
Čas izdaje: 2021
DOI: 10.3390/ijms22168610
ID: 14889992