Study of the role of oxidized lipid mediators and fatty acid beta-oxidation as modulators of ferroptosis sensitivity in cancer

• Grant number: 21/10153-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 01, 2022
• End date: February 28, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Sayuri Miyamoto
• Grantee: Adriano de Britto Chaves Filho
• Supervisor: Almut Schulze
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: German Cancer Research Center, Germany
• Associated to the scholarship: 20/08175-8 - Integration of quantitative lipidomic and oxy-lipidomic analysis to trace dysregulated pro-inflammatory pathways involved in infectious and neurodegenerative diseases, BP.PD

Abstract

Oxidized lipids are frequently linked to pathological conditions due to their role as modulators of inflammation and oxidative stress. More recently, oxidized lipids have been reported as key regulators of ferroptosis, a form of regulated cell death triggered by accumulation of lipid hydroperoxides in the cell membrane. Ferroptosis is under intensive investigation in diseases, with cancer being one of the most explored targets. Although some cancer lineages show high ferroptosis sensitivity, cancer cells have developed strategies to avoid ferroptotic cell death by promoting global lipid remodeling, as well as alterations in energy metabolism and the synthesis of oxidized lipids. Noteworthy, in a study performed by the Schulze group (DKFZ, Germany), it was observed that fatty acid beta-oxidation (FAO) can also modulate ferroptosis sensitivity in clear cell renal cell carcinoma (ccRCC). However, the specific role of oxidized lipid mediators and FAO in ferroptosis and cancer remains unclear. In two independent studies performed by our group, we have shown that linoleic acid (LA) and lipokines derived from it, referred as 9(10)- and 12(13)-DiHOME, are respectively: 1) preferentially and quantitatively beta-oxidized relative to other fatty acids (in a model of lipodystrophy) and 2) linked to an increase in energy expenditure in a model of amyotrophic lateral sclerosis (ALS). These results suggest that these compounds could be used to stimulate FAO and thereby allow to verify its relationship with ferroptosis in cellular models of cancer. In this project, we intend to explore the mechanisms by which oxidized lipids and FAO can act as modulators of ferroptosis sensitivity. In addition, we intend to investigate if LA and DiHOMEs are potential modulators of ferroptosis in cancer. (AU)