Xu Xue-Ming, Chen Yixin, Chen Jinguo, Yang Shanmin, Gao Feng, Underhill Charles B, Creswell Karen, Zhang Lurong
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA.
Cancer Res. 2003 Sep 15;63(18):5685-90.
A number of hyaluronan (HA) binding proteins such as soluble CD44, receptor for hyaluronan-mediated motility (RHAMM), and metastatin inhibit tumor growth and metastasis. To determine whether the HA binding motif is the element responsible for the antitumor effect of this family of proteins, we examined the biological activity of a 42-amino acid peptide (designated as BH-P) that contains three HA binding motifs [B(X(7))B] from human brain HA binding protein. In initial experiments with cultured cells, we found that synthetic BH-P inhibited the proliferation and colony formation of tumor cells. It also blocked the growth of tumors on the chorioallantoic membranes of 10-day chicken embryos. In addition, MDA-435 melanoma cells that had been transfected with an expression vector for BH-P grew at a slower rate in nude mice than the vector-alone transfectants. Final studies revealed that the BH-P could activate caspase-8, caspase-3, and poly(ADP-ribose) polymerase and trigger the apoptosis of tumor cells. Taken together, these results suggest that the HA binding motif that is present in HA binding proteins may be responsible for the antitumor effect exerted by the members of this family.
许多透明质酸（HA）结合蛋白，如可溶性CD44、透明质酸介导的运动受体（RHAMM）和转移抑制素，可抑制肿瘤生长和转移。为了确定HA结合基序是否是该蛋白家族抗肿瘤作用的关键因素，我们检测了一种42个氨基酸的肽（命名为BH-P）的生物学活性，该肽包含来自人脑HA结合蛋白的三个HA结合基序[B(X(7))B]。在最初的细胞培养实验中，我们发现合成的BH-P可抑制肿瘤细胞的增殖和集落形成。它还能抑制10日龄鸡胚绒毛尿囊膜上肿瘤的生长。此外，转染了BH-P表达载体的MDA-435黑色素瘤细胞在裸鼠中的生长速度比仅转染载体的细胞慢。最终研究表明，BH-P可激活半胱天冬酶-8、半胱天冬酶-3和聚（ADP-核糖）聚合酶，并触发肿瘤细胞凋亡。综上所述，这些结果表明，HA结合蛋白中存在的HA结合基序可能是该家族成员发挥抗肿瘤作用的原因。
