N-TERMINAL PORTION OF c-FOS AS A NEGATIVE DOMINANT OF THE PHOSPHOLIPIDS SYNTHESIS ACTIVATION: A NEW TARGET FOR GLIOBLASTOMAS.

PRUCCA CG; VELAZQUEZ FN; CARDOZO- GIZZI AM; CAPUTTO BL

Puerto Iguazu

Conferencia; 56th International Conference on the Bioscience of Lipids; 2015

Glioblastomas are one of the most aggressive type of brain cancer. Newly diagnosed patients with this type of tumor have poor prognosis and short survival period ~1 year. The actual therapeutic scheme for the treatment consist in reductive surgery followed by radio and chemotherapy. The search for novel strategies and new targets for treatment of these tumors is highly important. Previous results of our laboratory indicate that c-Fos, a well-known AP-1 transcription factor; is highly expressed in this type of tumors of the central nervous system contrasting with the low or absence of its expression in normal tissue. Moreover, it´s was reported that c-Fos is able to activate the phospholipid metabolism by activating key enzymes of the pathway of synthesis. Based in these observations we decide to exploit these properties as a new target for these tumors. We tested deletion mutants of c-Fos as negative dominants to block its action as activator of lipids synthesis. The overexpression of NA (aa 1-138), an deletion mutant of c-Fos, interfere in the interaction between c-Fos and one enzyme of the phospholipid metabolism (PI4KII􀄮) and its able to inhibits the proliferation of human glioblastoma cells (T98G) in vitro. In addition, we tested different portions of the NA domain and the results suggest that the interaction with PI4KII􀄮 involve the first 90 aminoacids of this domain; and the overexpression of two peptides compassing this portion diminish proliferation of T98G cells. The above-mentioned results suggest that the disruption of the of c-Fos´s phospholipid synthesis activation constitute a good target for the development of therapeutic strategies for the treatment of this highly malignant tumor.