Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy

Abstract

Objective: We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients.

Research design and methods: We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients. We also established the sensitivity of melanoma cell lines to DCA treatment, by assessing their metabolic alterations, proliferation and survival.

Results: We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status. Melanoma cell lines treated with DCA showed a shift in metabolism, that is, a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.

Conclusion: Our results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.

Keywords:

• dichloroacetate
• melanoma
• metabolism
• mTOR
• pyruvate dehydrogenase kinase

Acknowledgments

We are grateful to all of the patients who participated in this study as well as the physicians who provided clinical, pathological and follow-up information. We thank Dr Madalena Pinto, from CEQUIMED, Faculty of Pharmacy, University of Porto, Portugal, who kindly provided us A375 skin melanoma cell line, and Dr Marc Mareel, from the Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Belgium, who kindly provided us Mewo skin melanoma cell line. We thank Gabriela Almeida for the helpful technical advices regarding the PB assay. We also thank Prof Manuel Sobrinho Simões for the critical reading of this manuscript. H Pópulo and R Caldas contributed equally to this work.

Declaration of interest

This study was supported by the Portuguese Foundation for Science and Technology through Post-Doc grant to HP (Ref.: SFRH/BPD/85249/2012). Further funding was obtained from the project “Microenvironment, metabolism and cancer” that was partially supported by Programa Operacional Regional do Norte (ON.2 – O Novo Norte) under the Quadro de Referência Estratégico Nacional (QREN) and the Fundo Europeu de Desenvolvimento Regional (FEDER). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. This work was funded by FEDER funds through the Operational Programme for Competitiveness Factors – COMPETE and National Funds through the FCT, under the projects “PEst-C/SAU/LA0003/2013.” The authors disclose no potential conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes