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

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

Segunda, 01.06.2015

DCA was proposed as a possible cancer therapy, although it was unknown its possible use as cutaneous melanoma therapy. A team of IPATIMUP researchers published a study in Expert Opinion on Therapeutic Targets, where they evaluated the expression profile of pyruvate dehydrogenase kinase isoforms, the DCA targets, in a series of melanoma samples and nevi, and also established the sensitivity of melanoma cell lines to DCA treatment. They demonstrate that pyruvate dehydrogenase kinase expression may play a role in melanoma development and that DCA can be useful for cutaneous melanoma therapy.

 

Authors and Affiliations:

Helena Pópulo1,2,#, Regina Caldas1,2,3,#, José Manuel Lopes1,2, 4,5, Joana Pardal5, Valdemar Máximo1,2,4, Paula Soares1,2,4*

1 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), University of Porto, Porto, Portugal.

2 Institute for Research and Innovation in Health, University of Porto, Porto, Portugal (Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal).

3 Faculty of Medicine, University of Porto, Porto, Portugal.

4 Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal.

5 Service of Anatomic Pathology, Hospital São João, Porto, Portugal.

#- These authors contributed equally

*Corresponding author

 

Abstract:

We aimed to verify if there is evidence to consider 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. We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumours express the DCA targets, if this expression correlates with the activation of important signalling 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.

We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, being this expression 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, i.e. a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.

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.

 

Journal: Expert Opinion on Therapeutic Targets

 

Link: http://informahealthcare.com/doi/abs/10.1517/14728222.2015.1045416