Mauro Loredana, Pellegrino Michele, De Amicis Francesca, Ricchio Emilia, Giordano Francesca, Rizza Pietro, Catalano Stefania, Bonofiglio Daniela, Sisci Diego, Panno Maria Luisa, Andò Sebastiano
Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy.
Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy.
Cell Cycle. 2014;13(4):553-64. doi: 10.4161/cc.27455. Epub 2013 Dec 12.
Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, anti-inflammatory, antiatherogenic, and antiproliferative properties. In addition, it appears to play an important role also in the development and progression of several obesity-related malignancies, including breast cancer. Here, we demonstrated that adiponectin induces a dichotomic effect on breast cancer growth. Indeed, it stimulates growth in ERα+ MCF-7 cells while inhibiting proliferation of ERα- MDA-MB-231 cells. Notably, only in MCF-7 cells adiponectin exposure exerts a rapid activation of MAPK phosphorylation, which is markedly reduced when knockdown of the ERα gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ERα siRNA prevents this effect. Moreover, MAPK activation induced by adiponectin was reversed by IGF-IR siRNA. Coimmunoprecipitation studies show the existence of a multiprotein complex involving AdipoR1, APPL1, ERα, IGF-IR, and c-Src that is responsible for MAPK signaling activation in ERα+ positive breast cancer cells. It is well known that in addition to the rapid effects through non-genomic mechanisms, ERα also mediates nuclear genomic actions. In this concern, we demonstrated that adiponectin is able to transactivate ERα in MCF-7 cells. We showed the classical features of ERα transactivation: nuclear localization, downregulation of mRNA and protein levels, and upregulation of estrogen-dependent genes. Thus, our study clarifies the molecular mechanism through which adiponectin modulates breast cancer cell growth, providing evidences on the cell-type dependency of adiponectin action in relationship to ERα status.
脂联素是脂肪组织分泌的最丰富的蛋白质，具有胰岛素增敏、抗炎、抗动脉粥样硬化和抗增殖特性。此外，它似乎在包括乳腺癌在内的几种肥胖相关恶性肿瘤的发生和发展中也起着重要作用。 在这里，我们证明脂联素对乳腺癌生长具有二分效应。确实，它刺激雌激素受体α（ERα）阳性的MCF-7细胞生长，同时抑制ERα阴性的MDA-MB-231细胞增殖。值得注意的是，只有在MCF-7细胞中，脂联素暴露才会迅速激活丝裂原活化蛋白激酶（MAPK）磷酸化，而当ERα基因敲低时，这种磷酸化会明显降低。此外，脂联素在MCF-7细胞中诱导胰岛素样生长因子1受体（IGF-IR）迅速磷酸化，而使用ERα小干扰RNA（siRNA）可阻止这种效应。此外，IGF-IR siRNA可逆转脂联素诱导的MAPK激活。免疫共沉淀研究表明，在ERα阳性乳腺癌细胞中，存在一种由脂联素受体1（AdipoR1）、衔接蛋白APPL1、ERα、IGF-IR和原癌基因酪氨酸蛋白激酶c-Src组成的多蛋白复合物，该复合物负责MAPK信号激活。众所周知，除了通过非基因组机制产生的快速效应外，ERα还介导核基因组作用。在这方面，我们证明脂联素能够在MCF-7细胞中转录激活ERα。我们展示了ERα转录激活的经典特征：核定位、mRNA和蛋白质水平下调以及雌激素依赖性基因上调。因此，我们的研究阐明了脂联素调节乳腺癌细胞生长的分子机制，为脂联素作用与ERα状态相关的细胞类型依赖性提供了证据。
