Sobrexpressão da piruvato desidrogenase quinase indica o DCA como tendo potencial valor terapêutico em melanoma cutâneo

O DCA foi proposto como uma possível terapia para cancro, embora fosse desconhecida a sua possível aplicação em melanoma cutâneo. Uma equipa de investigadores do IPATIMUP publicou um estudo na revista Expert Opinion on Therapeutic Targets, onde avaliou a expressão das isoformas de piruvato desidrogenase quinase, as proteínas alvo do DCA, numa serie de melanoma cutâneos e nevos, e também determinou a sensibilidade de linhas celulares derivadas de melanoma cutâneo ao tratamento com DCA. Demonstraram que as proteínas piruvato desidrogenase quinase são sobrexpressas nas fases iniciais de melanoma cutâneo e que o tratamento com DCA inibe o crescimento e altera o metabolismo de linhas de melanoma podendo ser vantajoso no tratamento de melanoma cutâneo.

Autores e afiliações:

Helena Pópulo^1,2,#, Regina Caldas^1,2,3,#, José Manuel Lopes^{1,2, 4,5}, Joana Pardal⁵, Valdemar Máximo^1,2,4, Paula Soares^1,2,4*

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.

Revista: Expert Opinion on Therapeutic Targets

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