Expression of lactate transporters is associated with a worse prognosis in patients with melanoma

In the context of the metabolic reprogramming of tumor cells, in which an increase in glucose consumption and lactate production is observed, several proteins have its expression increased, including glucose transporters such as GLUT1 and lactate transporters, known as monocarboxylate transporters (MCTs). Exploiting this metabolic reprogramming as a potential therapeutic target has been identified as a promising strategy for the treatment of several tumor types, including melanomas. In this study, we assessed the expression of different proteins related to the metabolic alterations characteristic of tumor cells in samples from patients with melanoma as well as benign skin lesions. Among the various proteins analyzed, MCT4 and GLUT1 stood out because of its increased expression in metastases samples, compared to the expression in benign and primary tumor samples, while the expression of MCT1 and MCT4 stood out by their association with a lower overall survival of patients. The results of this study suggest a metabolic reprogramming in melanomas, favoring lower survival rates in patients with this type of tumor, which can be exploited for new therapeutic approaches.

Authors and Affiliations:

Céline Pinheiro^ab, Vera Miranda-Gonçalves^cd, Adhemar Longatto-Filho^bcde, Anna L. S. A. Vicente^b, Gustavo N. Berardinelli^b, Cristovam Scapulatempo-Neto^f, Ricardo F. A. Costa^a, Cristiano R. Viana^f, Rui M. Reis^bcd, Fátima Baltazar^cd & Vinicius L. Vazquez^bg

^a Barretos School of Health Sciences, Dr. Paulo Prata – FACISB, Barretos, São Paulo, Brazil

^b Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil

^c Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

^d ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal

^e Laboratory of Medical Investigation (LIM-14), School of Medicine, University of São Paulo, São Paulo, Brazil

^f Pathology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil

^g Surgery Department, Melanoma/Sarcoma, Barretos Cancer Hospital, Barretos, São Paulo, Brazil

Abstract:

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

Journal: Cell Cycle

Link: http://www.tandfonline.com/doi/full/10.1080/15384101.2016.1175258#.V4Yy7Fd578U