Glioblastoma multiforme is the most aggressive type of tumor of the CNS with an overall survival rate of approximately one year. Since this rate has not changed significantly over the last 20 years, the development of new therapeutic strategies for the treatment of these tumors is peremptory. The over-expression of the proto-oncogene c-Fos has been observed in several CNS tumors including glioblastoma multiforme and is usually associated with a poor prognosis. Besides its genomic activity as an AP-1 transcription factor, this protein can also activate phospholipid synthesis by a direct interaction with key enzymes of their metabolic pathways. Given that the amino-terminal portion of c-Fos (c-Fos-NA: amino acids 1–138) associates to but does not activate phospholipid synthesizing enzymes, we evaluated if c-Fos-NA or some shorter derivatives are capable of acting as dominant-negative peptides of the activating capacity of c-Fos. The over-expression or the exogenous administration of c-Fos-NA to cultured T98G cells hampers the interaction between c-Fos and PI4K2A, an enzyme activated by c-Fos. Moreover, it was observed a decrease in tumor cell proliferation rates in vitro and a reduction in tumor growth in vivo when a U87-MG-generated xenograft on nude mice is intratumorally treated with recombinant c-Fos-NA. Importantly, a smaller peptide of 92 amino acids derived from c-Fos-NA retains the capacity to interfere with tumor proliferation in vitro and in vivo. Taken together, these results support the use of the N-terminal portion of c-Fos, or shorter derivatives as a novel therapeutic strategy for the treatment of glioblastoma multiforme.

中文翻译：

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c-Fos破坏磷脂合成的激活会干扰胶质母细胞瘤细胞增殖

胶质母细胞瘤是中枢神经系统中最具侵略性的一种肿瘤，总生存率约为一年。由于该比率在过去20年中并未发生显着变化，因此必须开发用于治疗这些肿瘤的新治疗策略。在包括中型胶质母细胞瘤在内的多种中枢神经系统肿瘤中均观察到原癌基因c-Fos的过度表达，通常与不良预后有关。除了其作为AP-1转录因子的基因组活性外，该蛋白还可以通过与其代谢途径的关键酶直接相互作用来激活磷脂合成。鉴于c-Fos的氨基末端部分（c-Fos-NA：氨基酸1–138）与磷脂合成酶缔合但不激活，我们评估了c-Fos-NA或某些较短的衍生物是否能够充当c-Fos激活能力的显性负肽。对培养的T98G细胞过度表达或外源施用c-Fos-NA会阻碍c-Fos和PI4K2A（由c-Fos激活的酶）之间的相互作用。此外，当用重组c-Fos-NA瘤内治疗裸鼠上的U87-MG产生的异种移植物时，观察到体外肿瘤细胞增殖速率降低和体内肿瘤生长降低。重要的是，衍生自c-Fos-NA的92个氨基酸的较小肽保留了在体外和体内干扰肿瘤增殖的能力。综上所述，这些结果支持使用c-Fos的N端部分，