Benedetti Elisabetta, Antonosante Andrea, d'Angelo Michele, Cristiano Loredana, Galzio Renato, Destouches Damien, Florio Tiziana Marilena, Dhez Anne Chloé, Astarita Carlo, Cinque Benedetta, Fidoamore Alessia, Rosati Floriana, Cifone Maria Grazia, Ippoliti Rodolfo, Giordano Antonio, Courty José, Cimini Annamaria
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Department of Cell Biology, Université Paris-Est, UPEC, Créteil, France.
Oncotarget. 2015 Dec 8;6(39):42091-104. doi: 10.18632/oncotarget.5990.
Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma.
核仁素（NCL）在多种类型的癌症中高表达，是一个颇具吸引力的治疗靶点。它在肿瘤细胞的质膜上表达，这一特性被用作包括胶质母细胞瘤在内的多种人类癌症的标志物。在本研究中，我们研究了将靶向NCL作为治疗这种疾病的一种新治疗策略。为了探索这种可能性，我们使用人胶质母细胞瘤细胞原代培养物研究了NCL拮抗剂——多价假肽N6L的作用。在这个系统中，N6L根据NCL的定位以不同的敏感性抑制细胞生长。细胞周期分析表明，N6L诱导的生长抑制是由于G1/S期转换受阻以及细胞周期蛋白D1和B2表达下调。通过监测自噬标志物如p62和LC3II，我们证明N6L处理后自噬增强。此外，用N6L处理荷瘤小鼠可降低原位脑肿瘤模型中的体内肿瘤生长并延长小鼠存活时间。所得结果表明N6L具有抗增殖和促自噬作用，并指出其可能作为目前用于胶质母细胞瘤的标准治疗方案的辅助剂。
