The Role of Autophagy pathways in Ferroptosis in tumor cells

Abstract

Glioma is an extremely complex and challenging disease. It emerges as the most frequent primary tumor of the central nervous system. Remarkably, around half of glioma patients have the most aggressive form of the disease, glioblastoma. Patients diagnosed with glioblastoma have an average life expectancy of about 15 months following the standard treatment protocol, which involves tumor resection surgery, followed by radiotherapy and/or adjuvant chemotherapy, mainly based on temozolomide (TMZ). As revealed by the glioblastoma patient's average survival rates, this treatment is deemed palliative rather than curative due to the considerable ability of glioblastoma cells to resist therapies. Among many cellular processes involved in TMZ resistance we are particularly interested in autophagy and NRF2. Importantly, it has been shown that autophagy allows cancer cells to degrade proteins and organelles to provide energy for cellular processes sustaining their viability during chemotherapy. As for NRF2 many studies demonstrated that this transcriptional factor is crucial for drug detoxification and oxidative stress response to circumvent the effect of chemotherapies. Interestingly, recent reports indicate that these two processes are also involved in the cellular response to ferroptosis inducers. Ferroptosis is a new type of cell death that has the potential to be an important alternative to traditional treatments to glioblastoma. Nevertheless, there are still many gaps to be filled in order to fully reveal the mechanism behind this interplay. Thus, in order to obtain a substantial improvement on glioblastoma efficacy treatment, this proposal focuses on exploring the role of autophagy and NRF2, associated players, in ferroptosis in glioblastoma cells. We strongly believe that the knowledge obtained from the proposed work will help design more adequate and efficient chemotherapy strategies to treat glioblastoma patients.