Investigating the redox mechanisms of Vemurafenib resistance in Melanoma cells

Abstract

Melanoma is an extremely aggressive type of skin cancer. This characteristic is associated with a greater capacity for tumor metastasis and chemoresistance. Reactive oxygen species (ROS) contribute to the initiation of tumorigenesis, proliferation, invasion and metastasis. Metastasis is one of the most important factors related to a worse prognosis and is responsible for much of the morbidity related to solid tumors. The understanding of the role of these oxidants in the etiology and progression of melanoma is essential for the development of new therapeutic alternatives in the treatment of this disease. The family of NADPH oxidases, an enzyme dedicated to the generation of ROS, has been identified as an important source of oxidants in the progression and recurrence of melanoma. Among the isoforms, NADPH Nox4 and Nox2 are increased in melanoma metastatic patients and have been implicated in the survival of melanoma cells. Nox4 is related to the organization of the actin cytoskeleton and in the alterations in the phenotype of vascular smooth muscle cells. Nox2 has been implicated in the regulation of the NF-kB transcription factor that drives the expression of AXL, a receptor tyrosine kinase whose expression is correlated with chemotherapy resistance in patients with different types of cancer. In this project we intend to investigate the role of Nox2 and Nox4 in the progression and resistance of melanoma cells analyzing: survival, migration, invasion and colony formation capacity in melanoma cell lines sensitive and resistant to B-RAF inhibitors with distinct expression patterns of expression of Nox2 or Nox4. Additionally, in primary samples from melanoma patients we will investigate the prognostic impact of Nox2 and Nox4 expression in primary and metastatic tumors. Our preliminary data suggest that the expression of the Nox family of enzymes is correlated with melanoma progression. The project aims to investigate this new paradigm in the treatment of melanoma, providing alternatives to reduce its progression and resistance to chemotherapy. (AU)