Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities

• Published in: International journal of molecular sciences Vol. 23; no. 7; p. 3745
• Main Authors: Tiersma, Jiske F, Evers, Bernard, Bakker, Barbara M, Jalving, Mathilde, de Jong, Steven
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.03.2022; MDPI
• Subjects: Acidification; Cell division; Cell growth; Cell lines; Dehydrogenases; dichloroacetate; Dichloroacetic acid; Dichloroacetic Acid - pharmacology; Diclofenac; Drug dosages; Gene expression; Genotype & phenotype; Glucose; Glucose - metabolism; Glutaminase; Humans; Hypoxia; Isoforms; Kinases; Melanoma; Melanoma - drug therapy; metabolic reprogramming; Metabolism; Mutation; Oxygen consumption; Phosphorylation; Proteins; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Pyruvic acid; Spheroids; melanoma; metabolism; dichloroacetate; metabolic reprogramming
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23073745

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.