In vitro studies of a prolactin antagonist, hPRL-G129R in human breast cancer cells.
In vitro studies of a prolactin antagonist, hPRL-G129R in human breast cancer cells.
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DOI：
10.3892/ijo.18.1.25
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发表时间：
2001
影响因子：
5.2
通讯作者：
P. Ramamoorthy;R. Sticca;T. Wagner;W. Chen
中科院分区：
文献类型：
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作者：
P. Ramamoorthy;R. Sticca;T. Wagner;W. Chen
人催乳素（Human prolactin，hPRL）是一种重要的生存/生长因子，以自分泌/旁分泌的方式促进乳腺癌细胞的增殖。在我们最近的研究中，我们证明了具有单个氨基酸取代突变的hPRL拮抗剂（hPRL-G129 R）能够通过诱导细胞凋亡来抑制乳腺癌细胞增殖（1）。在这项研究中，进行了三个独立但相关的实验，关于hPRL-G129 R在乳腺癌细胞中的作用。我们研究了hPRL-G129 R诱导乳腺癌细胞凋亡的可能机制。转化生长因子（transforming growth factors，TGF）与雌激素、催乳素（PRL）等激素共同参与乳腺细胞的增殖和凋亡。我们首先研究了hPRL/hPRL-G129 R与TGF的关系。我们表明，hPRL能够下调TGF β 1（凋亡因子）的分泌和上调TGF α（生存因子）的分泌在T-47 D细胞中的剂量依赖性的方式。更重要的是，hPRL拮抗剂上调TGF β 1并下调TGF α分泌。当hPRL-G129 R与hPRL一起应用时，它阻断了hPRL的作用。其次，我们测试了半胱天冬酶在hPRL-G129 R诱导的细胞凋亡中的可能参与。我们已经表明，在T-47 D乳腺癌细胞中，hPRL-G129 R在250 ng/ml的浓度下激活胱天蛋白酶-3。第三，我们探索了抗肿瘤药物顺铂与hPRL-G129 R在T47 D乳腺癌细胞中的累加效应。我们表明，顺铂和hPRL-G129 R一起应用时，在T-47 D细胞中产生约40%的生长抑制。
Human prolactin (hPRL) has been shown to be one of the important survival/growth factors that promotes the proliferation of breast cancer cells in an autocrine/paracrine manner. In our recent studies, we demonstrated that a hPRL antagonist with a single amino acid substitution mutation (hPRL-G129R) was able to inhibit breast cancer cell proliferation via induction of apoptosis (1). In this study three independent yet related experiments were carried out regarding the effects of hPRL-G129R in breast cancer cells. We investigated the possible mechanism(s) of hPRL-G129R induced apoptosis in breast cancer cells. It is well documented that transforming growth factors (TGF) in conjunction with hormones such as estrogen and PRL play a major role in modulating the proliferation and apoptosis of mammary cells. We first investigated the relationships between hPRL/hPRL-G129R and TGFs. We show that hPRL is able to down-regulate TGF beta 1 (apoptotic factor) secretion and up-regulate TGF alpha (survival factor) secretion in a dose-dependent manner in T-47D cells. More importantly the hPRL antagonist up-regulates TGF beta 1 and down-regulates TGF alpha secretion. When hPRL-G129R was applied together with hPRL, it blocked the effects of hPRL. Secondly, we tested the possible involvement of caspases in hPRL-G129R induced apoptosis. We have shown that caspase-3 is activated by hPRL-G129R at a concentration of 250 ng/ml in T-47D breast cancer cells. Thirdly, we explored the additive effects of an anti-neoplastic drug, cisplatin, with the hPRL-G129R in T47D breast cancer cells. We show that cisplatin and hPRL-G129R when applied together resulted in about 40% growth inhibition in T-47D cells.