Astrocytomas are primary neoplasms of the Central Nervous System with astrocytic differentiation and graded from I to IV, based on histological criteria that have relation with prognosis. Treatment is primarily surgical, but unsatisfactory, because the tumors often recur and/or progress to higher grade neoplasms. The astrocytoma grade IV, also called glioblastoma, is the most common and aggressive type of glial tumors with poor response to chemotherapeutic agents, promoting a median survival of 14 months on affected individuals. Therefore, a better understanding of the behavior of these tumor types can be useful for developing new types of treatment.The most frequent molecular changes in astrocytomas include amplification/overexpression of the EGF and PDGF receptor, and deletion of the PTEN phosphatase. These changes activate the Ras/ERK1/2 and the PI3K/AKT signaling pathways in most of these tumor types. However, previous data of our group indicate that are an inverse correlation in the activation of these pathways in glioblastoma cell lines. Cells that have higher activation levels PI3K/AKT are those that have lower levels of Ras/ERK1/2 and vice versa, which may have important therapy implication. Thus, in this project we intend to confirm this finding using samples from human glioblastomas.A cellular mechanism directly controlled by Ras/ERK1/2 and PI3K/AKT pathways is the protein synthesis, a process essential for proliferation, migration and even cell death. The PI3K/AKT pathway stimulates translation of mRNAs through mTOR protein, which forms the complex mTORC1 and mTORC2. The first complex is susceptible to rapamycin inhibitor and is related to the control of translation, proliferation, autophagy and hypoxia. On the other hand, mTORC2 is insensitive to rapamycin and regulates events related to cell adhesion and migration. In previous studies we describe that patients with glioblastomas with higher mTORC2 protein expression and lower expression of phosphorylated AKT has better survival than those with the opposite molecular profile, suggesting that the presence of the complex mTORC2 can relate to less aggressive tumors. However, it is not known about the mechanisms by which these proteins influence the aggressiveness of glioblastomas. Thus, this project also intend to use glioblastoma cell lines and alter the expression of proteins forming complexes mTORC1 and 2, enable the observation of its influence on proliferation, invasion or susceptibility to drugs. The Ras/ERK1/2 signaling pathway, in turn, can affect the control of translation through both mTOR and RSK family of proteins. Evidences relate RSK1 and RSK2 to various aspects of the human cancer pathology. However, the role of RSKs in astrocytomas has never been explored. In previous work of our group we found that RSK inhibitors have an intense activity on the proliferation of glioblastoma cells, and are therefore candidates for new therapies. So, in this project we explore the role of RSKs in glioblastomas in preclinical trials, using RSK inhibitors, rapamycin and combinations of these drugs to verify their possible use in human glioblastomas.
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