Castillo Lilian Fedra, Rivero Ezequiel M, Goffin Vincent, Lüthy Isabel Alicia
Instituto Ángel H. Roffo, Av. San Martín 5481, Ciudad Autónoma de Buenos Aires, Argentina.
Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina.
Cell Signal. 2017 Jun;34:76-85. doi: 10.1016/j.cellsig.2017.03.003. Epub 2017 Mar 14.
Breast cancer is the most frequent malignancy among women worldwide. We have described the expression of α-adrenoceptors in breast cancer cell lines, associated with increased cell proliferation and tumor growth. A mitogenic autocrine/paracrine loop of prolactin (Prl) has been described in breast cancer cells. We hypothesized that the α-adrenergic enhancement of proliferation could be mediated, at least in part, by this Prl loop. In both T47D and MCF-7 cell lines, the incubation with the α-adrenergic agonist dexmedetomidine significantly increased Prl release into the culture medium (measured by the Nb2 bioassay), this effect being reversed by the α-adrenergic antagonist rauwolscine. No change in Prl receptors (PrlR) was observed by RT-qPCR in these cell lines. In IBH-6 cells a decrease in Prl secretion was observed at the lower dexmedetomidine concentration. The signaling pathways involved in ovine Prl (oPrl) and dexmedetomidine action were also assessed. Both compounds significantly activated STAT5 and ERK in all three cell lines. In T47D and MCF-7 cell lines also AKT was activated by both Prl and dexmedetomidine. We therefore describe the STAT5 phosphorylation by an α-adrenergic agonist, dexmedetomidine. In T47D cells, the α-adrenergic stimulation of cell proliferation is probably mediated, at least in part, by the Prl autocrine/paracrine loop, because this effect is abrogated by the specific PrlR antagonist Δ1-9-G129R-hPrl. The implication of Prl loop describes a novel mechanism of action of this GPCR.
乳腺癌是全球女性中最常见的恶性肿瘤。我们已经描述了α-肾上腺素能受体在乳腺癌细胞系中的表达，其与细胞增殖增加和肿瘤生长相关。在乳腺癌细胞中已描述了催乳素（Prl）的促有丝分裂自分泌/旁分泌环。我们推测α-肾上腺素能对增殖的增强作用可能至少部分由这个Prl环介导。在T47D和MCF-7细胞系中，与α-肾上腺素能激动剂右美托咪定孵育显著增加了Prl释放到培养基中（通过Nb2生物测定法测量），这种作用被α-肾上腺素能拮抗剂萝芙木碱逆转。通过RT-qPCR在这些细胞系中未观察到Prl受体（PrlR）的变化。在IBH-6细胞中，在较低的右美托咪定浓度下观察到Prl分泌减少。还评估了绵羊Prl（oPrl）和右美托咪定作用所涉及的信号通路。这两种化合物在所有三种细胞系中均显著激活了STAT5和ERK。在T47D和MCF-7细胞系中，Prl和右美托咪定也激活了AKT。因此，我们描述了α-肾上腺素能激动剂右美托咪定对STAT5的磷酸化作用。在T47D细胞中，α-肾上腺素能对细胞增殖的刺激作用可能至少部分由Prl自分泌/旁分泌环介导，因为这种作用被特异性PrlR拮抗剂Δ1-9-G129R-hPrl消除。Prl环的作用描述了这种GPCR的一种新作用机制。
