The role of peroxiredoxins 1 and 2 in melanoma heterogeneity

Abstract

Melanoma is the less common type of skin cancer, but it is the most aggressive. The most of patients harbor mutations in BRAF (V600E) protein, and its specific inhibitor vemurafenib has revolutionized the treatment of the disease. However, resistance to long-term therapy is recurrent, leading to treatment failure. Besides the acquired resistance, the many different mutations responsible for tumor heterogeneity leads to intrinsic resistance, in which cells are already resistant and are selected during treatment. This selection leads to the enrichment of resistant cells and poor prognosis. Tumor heterogeneity is not limited only to treatment resistance but also to the metabolic and functional changes that allow cells to survive in poor nutrient and oxygen environments. It is well accepted that tumor cells change their metabolism to obtain advantages in survival and proliferation. In this context, the transcriptional co-activator PGC1± plays a central role in the control of mitochondrial biogenesis and oxidative metabolism. Cells expressing more of this protein have higher mitochondrial activity and greater detoxification capacity of reactive oxygen species (ROS). Also, PGC1± is regulated by MITF, a transcription factor that integrates the melanoma biology and functions as a rheostat, defining phenotypes that can change as a function of the level of expression of this gene. Thus, there is a highly invasive but low proliferative phenotype (MITF low), and a less invasive but highly proliferative (MITF high) phenotype. The correlation between PGC1± and MITF is well accepted, but its relation to metabolic oxidative stress, metastasis, and treatment resistance in the context of tumor heterogeneity is poorly explored. Regarding oxidative stress, peroxiredoxins 1 and 2 (Prx1 and Prx2) are essential antioxidant proteins involved in redox signaling pathways and have its levels altered in melanoma, being related to metastasis and treatment resistance. Initial data from our group suggests a correlation between the levels of MITF, PGC1±, Prx1, and Prx2 among clonal subpopulations isolated from melanoma lineage. Considering the points presented, this project aims to characterize these subpopulations functionally by expression levels of MITF, PGC1±, Prx1 and Prx2 and its correlation to ROS production patterns, invasion, proliferation, and resistance to vemurafenib. The study of these aspects will lead to an understanding of the processes of oxidative metabolic changes, intrinsic resistance to therapy in subpopulations and may reveal a new mechanism to overcome treatment failure.