Cong Li, Gasser Jessica, Zhao Jessica, Yang Baofeng, Li Fanghong, Zhao Allan Z
Department of Cell Biology and Physiology, University of Pittsburgh, S-326, BSTWR, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA.
Endocr Relat Cancer. 2007 Sep;14(3):713-20. doi: 10.1677/ERC-07-0065.
Obesity is one of the well-established risk factors for endometrial cancer. Recent clinical studies have demonstrated that circulating adiponectin concentrations are inversely correlated with the incidence of endometrial carcinoma. Such epidemiological findings are consistent with the paradoxical observations that adiponectin levels are reduced in obesity. This study investigated the direct effects of adiponectin on two endometrial carcinoma cell lines, HEC-1-A and RL95-2. These cell lines express both variants of adiponectin receptors, adipo-R1 and adipo-R2. Adiponectin treatment leads to suppression of cell proliferation in both cell types, which is primarily due to the significant increase of cell populations at G(1)/G(0)-phase and to the induction of apoptosis. The inhibition of growth in these two cell lines appears to be mediated by different signaling pathways. Although adiponectin treatment markedly increases the phosphorylation (Thr172) of AMP-activated protein kinase alpha in both HEC-1-A and RL95-2 within 30 min, prolonged exposure (48 h) leads to inactivation of Akt as well as reduction of cyclin D1 protein expression in HEC-1-A cells. In contrast, similar treatment of RL95-2 cells with adiponectin, while having no effects on Akt activity and cyclin D1 expression, causes a decrease in cyclin E2 expression and the activity of mitogen-activated kinase (p42/44). We conclude that adiponectin exerts direct anti-proliferative effects on HEC-1-A and RL95-2 cells by inducing cell cycle arrest and apoptosis. Depending on the genotypes of the endometrial cancer cells, the inhibitory effects of adiponectin are associated with the reduction of different pro-growth regulators of cell cycle and signaling proteins. Our study thus provides a cellular mechanism underlying the linkages between endometrial cancer and obesity.
肥胖是子宫内膜癌公认的危险因素之一。最近的临床研究表明，循环脂联素浓度与子宫内膜癌的发病率呈负相关。这些流行病学发现与肥胖时脂联素水平降低这一矛盾观察结果一致。本研究调查了脂联素对两种子宫内膜癌细胞系HEC-1-A和RL95-2的直接作用。这些细胞系表达脂联素受体的两种变体，即脂联素受体1（Adipo-R1）和脂联素受体2（Adipo-R2）。脂联素处理导致两种细胞类型的细胞增殖均受到抑制，这主要是由于G(1)/G(0)期细胞数量显著增加以及细胞凋亡的诱导。这两种细胞系生长的抑制似乎是由不同的信号通路介导的。尽管脂联素处理在30分钟内显著增加了HEC-1-A和RL95-2细胞中AMP激活的蛋白激酶α（AMPKα）的磷酸化（苏氨酸172），但长时间暴露（48小时）会导致HEC-1-A细胞中Akt失活以及细胞周期蛋白D1蛋白表达减少。相比之下，用脂联素对RL95-2细胞进行类似处理，虽然对Akt活性和细胞周期蛋白D1表达没有影响，但会导致细胞周期蛋白E2表达和丝裂原活化激酶（p42/44）活性降低。我们得出结论，脂联素通过诱导细胞周期停滞和细胞凋亡对HEC-1-A和RL95-2细胞发挥直接的抗增殖作用。根据子宫内膜癌细胞的基因型，脂联素的抑制作用与细胞周期和信号蛋白的不同促生长调节因子的减少有关。因此，我们的研究提供了子宫内膜癌与肥胖之间联系的细胞机制。
