Targeted Investigation of Tricarboxylic Acid (TCA) Cycle Metabolites in Women with Breast Cancer Undergoing Combined Training

• Grant number: 24/21103-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2025
• End date: January 31, 2027
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Miguel Soares Conceição
• Grantee: Cíntia Cristiani
• Host Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil
• Associated research grant: 21/01424-5 - Effects of combined physical training in women with Breast Cancer submitted to chemotherapy, AP.JP

Abstract

Physical exercise performed systematically, known as physical training, specifically combined training (CT), has been investigated for its role in reducing cancer mortality. CT, which includes both strength and aerobic exercises, increases muscle mass and aerobic fitness in women with breast cancer-variables that are critical for reducing mortality. Furthermore, recent studies have shown that physical training can affect tumor metabolism, making it less aggressive.Tumor metabolism is distinctive because cancer cells tend to convert glucose into lactate, regardless of the presence of oxygen, a phenomenon known as the Warburg effect. While normal cells utilize oxidative phosphorylation in the mitochondria to produce energy, cancer cells prefer aerobic glycolysis. This metabolic reprogramming allows tumor cells to rapidly produce energy, promoting their uncontrolled growth.On the other hand, evidence also indicates that exercise is associated with a shift in the tumor's lactate dehydrogenase (LDH) isoenzyme profile toward LDH-1. This occurs alongside a decrease in LDHA expression, an increase in LDHB expression, and a concomitant reduction in tumor lactate levels and monocarboxylate lactate transporter 1 (MCT-1). Together, these findings suggest that physical exercise modifies tumor metabolism by reducing lactate production, increasing lactate utilization, and/or improving lactate clearance from the body. This could result in less lactate accumulation in tumor tissues, creating an environment less favorable for cancer growth.Thus, it is necessary to investigate the metabolites generated by physical exercise to understand whether it can affect tumor metabolism. For this purpose, metabolomics appears to be the most appropriate tool. Metabolomics, using liquid chromatography coupled with mass spectrometry (LC-MS), is a sensitive and robust method, essential for detecting and monitoring metabolites in various biological samples.Untargeted metabolomics aims to detect as many metabolites as possible without a specific target, functioning as a hypothesis generator. On the other hand, targeted metabolomics focuses on a predefined set of molecules of interest, such as metabolites from the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle. The TCA cycle is a series of chemical reactions aimed at oxidizing acetyl-CoA (acetyl coenzyme A), obtained from the breakdown of carbohydrates, fatty acids, and amino acids, producing carbon dioxide (CO¿), energy, and molecules of NADH and FADH2, which feed the mitochondrial respiratory chain.Therefore, the targeted approach is more sensitive and reproducible, being associated with hypothesis confirmation. In this context, considering the evidence demonstrating the potential of physical exercise to alter metabolism, it is essential to investigate in greater detail the possible exercise-induced alterations, particularly in TCA cycle metabolites, in the blood of breast cancer patients undergoing CT.