Caliceti Cristiana, Zambonin Laura, Rizzo Benedetta, Fiorentini Diana, Vieceli Dalla Sega Francesco, Hrelia Silvana, Prata Cecilia
Department of Clinical and Experimental Medicine, University of Ferrara, Via Fossato di Mortara 66, 44121 Ferrara, Italy.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Biomed Res Int. 2014;2014:857504. doi: 10.1155/2014/857504. Epub 2014 Mar 11.
Caveolae/lipid rafts are membrane-rich cholesterol domains endowed with several functions in signal transduction and caveolin-1 (Cav-1) has been reported to be implicated in regulating multiple cancer-associated processes, ranging from tumor growth to multidrug resistance and angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) and Cav-1 are frequently colocalized, suggesting an important role played by this interaction on cancer cell survival and proliferation. Thus, our attention was directed to a leukemia cell line (B1647) that constitutively produces VEGF and expresses the tyrosine-kinase receptor VEGFR-2. We investigated the presence of VEGFR-2 in caveolae/lipid rafts, focusing on the correlation between reactive oxygen species (ROS) production and glucose transport modulation induced by VEGF, peculiar features of tumor proliferation. In order to better understand the involvement of VEGF/VEGFR-2 in the redox signal transduction, we evaluated the effect of different compounds able to inhibit VEGF interaction with its receptor by different mechanisms, corroborating the obtained results by immunoprecipitation and fluorescence techniques. Results here reported showed that, in B1647 leukemia cells, VEGFR-2 is present in caveolae through association with Cav-1, demonstrating that caveolae/lipid rafts act as platforms for negative modulation of VEGF redox signal transduction cascades leading to glucose uptake and cell proliferation, suggesting therefore novel potential targets.
小窝/脂筏是富含膜胆固醇的结构域，在信号转导中具有多种功能，据报道小窝蛋白-1（Cav-1）参与调节多种癌症相关过程，从肿瘤生长到多药耐药和血管生成。血管内皮生长因子受体-2（VEGFR-2）和Cav-1经常共定位，表明这种相互作用在癌细胞存活和增殖中起重要作用。因此，我们将注意力转向一种白血病细胞系（B1647），该细胞系组成性产生VEGF并表达酪氨酸激酶受体VEGFR-2。我们研究了小窝/脂筏中VEGFR-2的存在情况，重点关注活性氧（ROS）产生与VEGF诱导的葡萄糖转运调节之间的相关性，这是肿瘤增殖的独特特征。为了更好地理解VEGF/VEGFR-2在氧化还原信号转导中的作用，我们评估了不同化合物通过不同机制抑制VEGF与其受体相互作用的效果，并通过免疫沉淀和荧光技术证实了所得结果。这里报道的结果表明，在B1647白血病细胞中，VEGFR-2通过与Cav-1结合存在于小窝中，表明小窝/脂筏作为VEGF氧化还原信号转导级联反应的负调节平台，导致葡萄糖摄取和细胞增殖，因此提示了新的潜在靶点。
