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...
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2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| author | Nives Škorja Milić Klemen Dolinar Katarina Miš Urška Matkovič Maruša Bizjak Mojca Pavlin Matej Podbregar Sergej Pirkmajer |
| author_facet | Nives Škorja Milić Klemen Dolinar Katarina Miš Urška Matkovič Maruša Bizjak Mojca Pavlin Matej Podbregar Sergej Pirkmajer |
| author_sort | Nives Škorja Milić |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:45:08Z |
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| id | doaj.art-c7fbe9b89306493baf98c8fb4b271a3a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:45:08Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c7fbe9b89306493baf98c8fb4b271a3a2023-11-22T07:57:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216861010.3390/ijms22168610Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1αNives Škorja Milić0Klemen Dolinar1Katarina Miš2Urška Matkovič3Maruša Bizjak4Mojca Pavlin5Matej Podbregar6Sergej Pirkmajer7Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaInstitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaInstitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaInstitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaGroup for Nano and Biotechnological Applications, Faculty of Electrical Engineering, University of Ljubljana, 1000 Ljubljana, SloveniaGroup for Nano and Biotechnological Applications, Faculty of Electrical Engineering, University of Ljubljana, 1000 Ljubljana, SloveniaInstitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaInstitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaInhibition 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.https://www.mdpi.com/1422-0067/22/16/8610dichloroacetatepyruvate dehydrogenase kinasepyruvate dehydrogenase complexcancerskeletal muscle cellsmyotubes |
| spellingShingle | Nives Škorja Milić Klemen Dolinar Katarina Miš Urška Matkovič Maruša Bizjak Mojca Pavlin Matej Podbregar Sergej Pirkmajer Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α International Journal of Molecular Sciences dichloroacetate pyruvate dehydrogenase kinase pyruvate dehydrogenase complex cancer skeletal muscle cells myotubes |
| title | Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α |
| title_full | Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α |
| title_fullStr | Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α |
| title_full_unstemmed | Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α |
| title_short | Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α |
| title_sort | suppression of pyruvate dehydrogenase kinase by dichloroacetate in cancer and skeletal muscle cells is isoform specific and partially independent of hif 1α |
| topic | dichloroacetate pyruvate dehydrogenase kinase pyruvate dehydrogenase complex cancer skeletal muscle cells myotubes |
| url | https://www.mdpi.com/1422-0067/22/16/8610 |
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