N-TERMINAL PORTION OF C-FOS AS A NEW THERAPUETIC STRATEGY FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME TUMORS

CAPUTTO, BEATRIZ L.; PRUCCA, CÉSAR G.; VELAZQUEZ, FABIOLA; RACCA, A.C.

Congreso; SAIB 2017 - Reunión conjunta de Sociedades; 2017

The survival time for patients with Glioblastoma multiforme hasnot improved significantly over the last ten years with an averagesurvival period for these patients of ~1 year after diagnosis, thusrepresenting the most aggressive and lethal type of tumors of thecentral nervous system (CNS). We found that in addition to its roleas an AP1 transcription factor, c-Fos activates the rate of synthesisof phospholipids, key components for membrane biogenesis, at theendoplasmic reticulum. Furthermore, we determined that the regulationof this metabolism is implicated in tumor biology, sustainingthe exacerbated growth characteristic of brain tumor cells. We alsofound c-Fos overexpressed in brain tumors co-localizing with componentsof the endoplasmic reticulum contrasting with the lack ofdetectable expression of c-Fos in normal CNS. These results pointto c-Fos as a potential new target for glioblastoma treatment. Consequently,the aim of the present work was to test N-terminal deletionmutants of c-Fos as possible negative dominants of the lipidsynthesis activation capacity of c-Fos. Using several in vitro approaches,(transfection, profection of recombinant proteins and generationof stable cell lines) we identified negative dominants whoseoverexpression inhibits proliferation of T98G cells, we evaluate theinduction of cell death and we dissect the domains of N-terminalportion of c-Fos (NA) involved in the physical interaction of c?Foswith enzymes that it activates such as phosphatidylinositol 4 kinaseIIα (PI4KIIα) using FRET microscopy. Moreover, the negative dominanceof NA resulted effective in an in vivo model of CNS tumorsusing T98G xenografts on immunodeficient NOD-SCID mice. Takentogether, our results point to specific domains of NA as possible newtherapeutic strategies for the treatment of glioblastoma multiforme.