Giorgini Simona, Trisciuoglio Daniela, Gabellini Chiara, Desideri Marianna, Castellini Laura, Colarossi Cristina, Zangemeister-Wittke Uwe, Zupi Gabriella, Del Bufalo Donatella
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Mol Cancer Res. 2007 Aug;5(8):761-71. doi: 10.1158/1541-7786.MCR-07-0088.
In this paper, we investigated whether bcl-xL can be involved in the modulation of the angiogenic phenotype of human tumor cells. Using the ADF human glioblastoma and the M14 melanoma lines, and their derivative bcl-xL-overexpressing clones, we showed that the conditioned medium of bcl-xL transfectants increased in vitro endothelial cell functions, such as proliferation and morphogenesis, and in vivo vessel formation in Matrigel plugs, compared with the conditioned medium of control cells. Moreover, the overexpression of bcl-xL induced an increased expression of the proangiogenic interleukin-8 (CXCL8), both at the protein and mRNA levels, and an enhanced CXCL8 promoter activity. The role of CXCL8 on bcl-xL-induced angiogenesis was validated using CXCL8-neutralizing antibodies, whereas down-regulation of bcl-xL through antisense oligonucleotide or RNA interference strategies confirmed the involvement of bcl-xL on CXCL8 expression. Transient overexpression of bcl-xL led to extend this observation to other tumor cell lines with different origin, such as colon and prostate carcinoma. In conclusion, our results showed that CXCL8 modulation by bcl-xL regulates tumor angiogenesis, and they point to elucidate an additional function of bcl-xL protein.
在本文中，我们研究了bcl-xL是否参与人类肿瘤细胞血管生成表型的调节。使用ADF人胶质母细胞瘤和M14黑色素瘤细胞系及其过表达bcl-xL的衍生克隆，我们发现与对照细胞的条件培养基相比，bcl-xL转染子的条件培养基增强了体外内皮细胞功能，如增殖和形态发生，以及体内基质胶栓中的血管形成。此外，bcl-xL的过表达在蛋白质和mRNA水平上均诱导促血管生成的白细胞介素-8（CXCL8）表达增加，并且增强了CXCL8启动子活性。使用CXCL8中和抗体验证了CXCL8在bcl-xL诱导的血管生成中的作用，而通过反义寡核苷酸或RNA干扰策略下调bcl-xL证实了bcl-xL参与CXCL8表达。bcl-xL的瞬时过表达将这一观察结果扩展到其他不同来源的肿瘤细胞系，如结肠癌和前列腺癌。总之，我们的结果表明bcl-xL对CXCL8的调节作用调控肿瘤血管生成，并且指出了bcl-xL蛋白的另一种功能。
