Characterization of the role of protein pyruvate dehydrogenase kinase 3 (PDK3) in melanoma

• Grant number: 22/13443-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Céline Marques Pinheiro
• Grantee: Caroline Miho Shibuya
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

Different tumor cells present a metabolic reprogramming characterized by the switch of the main energy pathway (oxidative phosphorylation) to glycolysis, even in the presence of sufficient oxygen, denominated the Warburg effect. Pyruvate dehydrogenase kinase (PDK) plays a role in this metabolic reprogramming, due to its inhibitory action on the pyruvate dehydrogenase complex, diverting the flow of pyruvate from mitochondria to lactate production. In this context, PDK3, one of the 4 PDK isoforms, is described as overexpressed in melanomas, being associated with increased cell survival and chemotherapy resistance. Melanoma constitutes 5% of all skin cancers and has a high mortality rate. The most common molecular change in this type of tumor is V600E mutation in BRAF gene, with vemurafenib being a target therapy used in BRAFV600E-melanoma treatment. Despite new strategies are being used against melanoma, poor prognosis remains in advanced stage. Therefore, the present study aims to characterize PDK3 role in melanoma aggressiveness and in the resistance of melanoma cells to vemurafenib. This characterization will be performed through in vitro assays to evaluate cell viability, proliferation, colony formation capacity, apoptosis, migration and invasion of melanoma cells after PDK3 knockdown with siRNA, in order to explore PDK3 as a possible therapeutic strategy in melanoma.