Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells.
Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells.
复制标题
DOI：
--
复制
发表时间：
1997-07
期刊：
影响因子：
11.2
通讯作者：
M. Guvakova;E. Surmacz
中科院分区：
文献类型：
--
作者：
M. Guvakova;E. Surmacz
胰岛素样生长因子I受体（IGF-IR）参与乳腺癌细胞生长的控制。他莫昔芬（Tamoxifen，Tam）是一种非甾体类抗雌激素药物，其细胞生长抑制活性部分是通过干扰IGF-I-R依赖的细胞增殖来介导的，但Tam对IGF-IR细胞内信号传导的影响尚未阐明。因此，我们研究了Tam如何改变雌激素受体阳性MCF-7乳腺癌细胞和过表达IGF-IR（MCF-7/IGF-IR细胞）或其主要底物IRS-1（MCF-7/IRS-1细胞）的MCF-7衍生克隆中的IGF-IR信号通路。MCF-7/IGF-IR和MCF-7/IRS-1细胞表现出大大降低的雌激素生长需求，但保留雌激素受体并表达对抗雌激素的敏感性，与亲本细胞相当。在所有测试的细胞系中，不管IGF信号的放大，用10 nM Tam处理4天产生类似的细胞抑制作用。在MCF-7和MCF-7/IGF-IR细胞中，Tam的生长抑制与IGF-I存在时IGF-IR酪氨酸磷酸化的降低相关;然而，IGF-IR的基础水平保持不受影响。此外，Tam抑制IRS-1的基础和IGF-I诱导的酪氨酸磷酸化，这伴随着IRS-1相关的磷脂酰肌醇3 '-激酶活性的下调和IRS-1/生长因子受体结合蛋白2（GRB 2）结合的减少。相反，在相同的治疗下，Src-同源/胶原蛋白（SHC; IGF-IR的另一种底物）的酪氨酸磷酸化和SHC/GRB 2结合升高。Tam未改变IGF-IR和IRS-1的蛋白水平，而SHC蛋白表达不受影响或适度降低。总之，这项工作提供了第一个证据表明，在MCF-7细胞中，Tam的细胞生长抑制作用与IGF-IR信号转导的调节有关，特别是与：（a）IGF-I诱导的IGF-IR酪氨酸磷酸化的下调;（B）IRS-1/磷脂酰肌醇3 '-激酶信号转导的抑制;和（c）SHC酪氨酸磷酸化的上调和SHC/GRB 2结合的增加有关。据推测，IRS-1的去磷酸化可能是Tam细胞生长抑制活性的主要影响因素。
The insulin-like growth factor I receptor (IGF-IR) is involved in the control of breast cancer cell growth. The cytostatic activity of tamoxifen (Tam), a nonsteroidal antiestrogen, is partially mediated through interference with IGF-I-R-dependent proliferation, yet the effects of Tam on IGF-IR intracellular signaling have never been elucidated. Consequently, we investigated how Tam modifies the IGF-IR signaling pathway in estrogen receptor-positive MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR (MCF-7/IGF-IR cells) or its major substrate, IRS-1 (MCF-7/IRS-1 cells). MCF-7/IGF-IR and MCF-7/IRS-1 cells exhibit greatly reduced estrogen growth requirements but retain estrogen receptors and express sensitivity to antiestrogens comparable to that in the parental cells. In all tested cell lines, regardless of the amplification of IGF signaling, a 4-day treatment with 10 nM Tam produced a similar cytostatic effect. In MCF-7 and MCF-7/IGF-IR cells, growth inhibition by Tam was associated with the reduced tyrosine phosphorylation of the IGF-IR in the presence of IGF-I; however, the basal level of the IGF-IR remained unaffected. Moreover, Tam inhibited both basal and IGF-I-induced tyrosine phosphorylation of IRS-1, which was accompanied by down-regulation of IRS-1-associated phosphatidylinositol 3'-kinase activity and reduced IRS-1/growth factor receptor-bound protein 2 (GRB2) binding. In contrast, under the same treatment, tyrosine phosphorylation of Src-homology/collagen proteins (SHC; another substrate of the IGF-IR) and SHC/GRB2 binding were elevated. The protein levels of the IGF-IR and IRS-1 were not modified by Tam, whereas SHC protein expression was either not affected or moderately decreased by the treatment. In summary, this work provides the first evidence that in MCF-7 cells, cytostatic effects of Tam are associated with the modulation of IGF-IR signaling, specifically with: (a) down-regulation of IGF-I-induced tyrosine phosphorylation of the IGF-IR; (b) inhibition of IRS-1/phosphatidylinositol 3'-kinase signaling; and (c) up-regulation of SHC tyrosine phosphorylation and increased SHC/GRB2 binding. It is hypothesized that dephosphorylation of IRS-1 could be a major contributing factor in Tam cytostatic activity.