Involvement of uric acid in lipid remodeling in tumor cell survival and proliferation

Abstract

Uric acid is the end product of purine metabolism in humans. Spite of being considered the main antioxidant in plasma, uric acid can be oxidized by inflammatory and extracellular matrix heme-peroxidases, generating urate free radical, which can trigger free radical chain reactions and lipid peroxidation. Interestingly, in the tumor milieu, both types of heme-peroxidases are abundantly expressed and the oxidation of uric acid in this context could explain its correlation with tumor progression and incidence. Preliminary lipidome data from our group showed that uric acid increased the levels of 19 different types of triacylglycerol (TAGs), 2 different types of diacylglycerol (DAG) and membrane cholesterol in infected neutrophil. This was related with the formation of lipid droplets (LD), cytoplasmic organelles rich in neutral lipids. LD accumulation is associated with cell survival and growth in cancer because it protects against oxidative stress. Since oxidation of uric acid is prone to happen in tumor tissues and that it lead to oxidative stress, it could drive lipid remodeling and LD formation and tumor resistance. Therefore, the general objective of this project is to elucidate changes in lipid metabolism and the role of uric acid in remodeling lipids associated with mechanism of cell survival in cancer. Additionally, we intend to address lipid composition and metabolic processes that contribute to the production and scavenging of oxidized lipids, such LD biogenesis, to find new biomarkers involved in the progression of glioblastoma and lung adenocarcinoma. Nonetheless, capturing details in the molecular species of lipids that might be involved in the mechanisms of resistance against oxidative stress, including LD formation, is analytically challenging and awaits investigation. In view of this, the use of sophisticated tools capable of characterizing lipid remodeling and oxidized lipids, and its location is highly relevant to understand the implications with cancer progression and recurrence. Dr Carsten Hopf's group at the Center for Mass Spectrometry and Optical Spectroscopy, has been developing analytical methods using advanced technical in MALDI mass spectrometry (MS)-based imaging. Their approaches offer new opportunities to associate identification with location, through MS imaging. To attend the main objective, lipidome and oxidized lipids will be investigated using LC-trapped ion mobility (tims)TOF MS (LC-ESI-MSMS) technology combined with MALDI imaging to associate metabolite location with cancer recurrence or resistance therapies. In summary, this work will shed light on the mechanisms involving lipid remodeling and oxidized lipids in glioblastoma and lung cancer and the influence of uric acid in this process. The use of innovative MS technologies will push forward our understanding of the role of lipids in such a complex pathology and might bring new insights into potential cancer diagnostics and treatment. (AU)