Du Jun, Yang Shuang, Wang Zhaoqi, Zhai Chunli, Yuan Wei, Lei Rongyue, Zhang Jie, Zhu Tianhui
Medical College of Nankai University, Tianjin, China.
J Cell Biochem. 2008 Apr 1;103(5):1584-97. doi: 10.1002/jcb.21547.
Breast carcinoma is one of the most common malignant tumors and has become a more common cancer in women. BMP6 was abnormally expressed in breast cancer specimens and cell lines. However, the contribution of BMP6 in promoting breast cancer progression remains unknown. The purpose of our study was to establish whether expression of BMP6 in breast cancer cells affect their proliferation or apoptosis and the mechanism. We found that BMP6 inhibited proliferation of MDA-MB-231 cells and blocked cell cycle at G(0)/G(1) stage. BMP6 also inhibited serum deprivation induced apoptosis in MDA-MB-231 cells. At the 4 days of serum starvation, BMP6 reduced the percentage of caspase-3 positive cells from 49% to 21%, BMP6 also reduced sub-G(1) peak induced by serum starvation. In contrast, BMP6 significantly enhanced survivin expression both at mRNA and protein levels. Dominant negative-survivin and Antisense-survivin impaired BMP6 induced antiapoptotic effect. BMP6 enhanced survivin expression at the transcription level in a Smad-dependent manner. BMP6 also played its antiapoptotic effect through activation p38 MAPK signal pathway, independent of smad/survivin pathway. These results suggested that BMP6 induced cell cycle arrest in estrogen-insensitive breast cancer cells. BMP6 inhibits stress-induced apoptosis via both Smad and p38 signal pathways.
乳腺癌是最常见的恶性肿瘤之一，已成为女性中更为常见的癌症。骨形态发生蛋白6（BMP6）在乳腺癌标本和细胞系中异常表达。然而，BMP6在促进乳腺癌进展中的作用仍不清楚。我们研究的目的是确定BMP6在乳腺癌细胞中的表达是否会影响其增殖或凋亡及其机制。我们发现BMP6抑制MDA-MB-231细胞的增殖并将细胞周期阻滞在G(0)/G(1)期。BMP6还抑制血清剥夺诱导的MDA-MB-231细胞凋亡。在血清饥饿4天时，BMP6将半胱天冬酶-3阳性细胞的百分比从49%降至21%，BMP6还减少了血清饥饿诱导的亚G(1)峰。相反，BMP6在mRNA和蛋白质水平上均显著增强生存素的表达。显性负性生存素和反义生存素削弱了BMP6诱导的抗凋亡作用。BMP6以Smad依赖的方式在转录水平增强生存素的表达。BMP6还通过激活p38丝裂原活化蛋白激酶信号通路发挥其抗凋亡作用，独立于Smad/生存素通路。这些结果表明，BMP6诱导雌激素不敏感乳腺癌细胞的细胞周期停滞。BMP6通过Smad和p38信号通路抑制应激诱导的凋亡。
