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Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities
Jiske F Tiersma1, Bernard Evers2, Barbara M Bakker2
1Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Abstract:
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 IC50 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.
Insights
Dichloroacetate (DCA) and other pyruvate dehydrogenase kinase (PDK) inhibitors reduce melanoma cell growth by reprogramming metabolism. DCA synergizes with glutaminase and monocarboxylate transporter inhibitors, revealing new therapeutic strategies.
Area of Science:
- Biochemistry
- Oncology
- Metabolic pathways
Background:
- Melanoma exhibits high glucose uptake, partly due to elevated pyruvate dehydrogenase kinase (PDK).
- PDK is a potential therapeutic target for melanoma treatment.
- Targeting PDK may inhibit melanoma cell growth and uncover metabolic vulnerabilities.
Purpose of the Study:
- To investigate the effects of PDK inhibition on melanoma cell glucose uptake and growth.
- To identify synergistic effects of PDK inhibition with other metabolic drugs.
- To explore metabolic reprogramming induced by PDK inhibition in melanoma.
Main Methods:
- Utilized melanoma cell lines (MeWo, SK-MEL-2) treated with PDK inhibitors (dichloroacetate [DCA], AZD7545) and PDK isoform knockdown.
- Assessed cell viability (IC50 values) and measured metabolic parameters (PDH phosphorylation, oxygen consumption rate:extracellular acidification rate [OCR:ECAR] ratio).
- Evaluated synergistic growth inhibition with glutaminase inhibitor (CB-839) and monocarboxylate transporter (MCT) inhibitor (diclofenac).
Main Results:
- DCA demonstrated varying sensitivity across melanoma cell lines (IC50: 13.3–27.0 mM).
- DCA significantly reduced PDH phosphorylation and increased the OCR:ECAR ratio.
- DCA exhibited synergistic effects with CB-839 (2- to 5-fold) and diclofenac (3- to 8-fold), with diclofenac also impacting ECAR.
Conclusions:
- Dichloroacetate (DCA) inhibits melanoma cell proliferation by reprogramming cellular metabolism.
- PDK inhibition, particularly with DCA, shows synergistic potential with other metabolic drugs like CB-839 and diclofenac.
- Targeting PDK and related metabolic pathways offers promising therapeutic strategies for melanoma.
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