Vellon Luciano, Menendez Javier A, Lupu Ruth
Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA.
Mol Carcinog. 2006 Oct;45(10):795-804. doi: 10.1002/mc.20242.
In addition to their role in cell migration and adhesion, integrins elicit a series of transduction events that regulate cell-cycle progression and apoptosis in a process known as "outside-in" signaling. A second mode of integrin regulation known as "inside-out" signaling, in which the activation of major cell transduction cascades can influence the activation status of some integrins, has also been described. Here, we have assessed the role of the extracellular signal-regulated kinase (ERK1)/ERK2, mitogen-activated protein kinase (MAPK), and phospoinositide 3-kinase (PI-3'K) signaling pathways in the expression and function of alpha(v)beta(3) integrin in breast cancer models. Pharmacological inhibition of MEK1 and MEK2 with U0126 drastically increased the levels of alpha(v)beta(3) in Heregulin (HRG)-overexpressing MDA-MB-231 cells (231/WT, 231/VEC) and derivatives transfected with the antisense orientation of the HRG-beta2 full length cDNA (231/ASPOOL, 231/AS31). Interestingly, this was related to a significant decrease of viability and of the S- and G2/M subcompartment of the cell cycle in MDA MB 231 cells in response to U0126. Furthermore, specific inhibition of the PI-3'K pathway with LY294002 also induced an increase of alpha(v)beta(3) levels but to a lesser extent. Moreover, pretreatment of MDA-MB-231 cells with U0126 antagonized the effects of small peptidomimetic alpha(v)beta(3) antagonists. Remarkably, inhibition of the PI-3'K/AKT pathway did not exert the same effects, thus suggesting that the "outside-in" as well as the "inside-out" alpha(v)beta(3)-mediated signaling goes primarily through the ERK1/ERK2 MAPK pathway in MDA MB 231 breast cancer cells. Collectively, these results strongly suggest the existence of a bidirectional molecular connection alpha(v)beta(3)-ERK1/ERK2 MAPK that would regulate breast cancer cells survival and proliferation.
整合素除了在细胞迁移和黏附中发挥作用外，还能引发一系列转导事件，在一个被称为“由外向内”信号传导的过程中调节细胞周期进程和细胞凋亡。还描述了整合素调节的第二种模式，即“由内向外”信号传导，其中主要细胞转导级联反应的激活可影响某些整合素的激活状态。在此，我们评估了细胞外信号调节激酶（ERK1）/ERK2、丝裂原活化蛋白激酶（MAPK）和磷酸肌醇3激酶（PI-3'K）信号通路在乳腺癌模型中α(v)β(3)整合素表达和功能中的作用。用U0126对MEK1和MEK2进行药理学抑制，可显著增加过表达Heregulin（HRG）的MDA-MB-231细胞（231/WT、231/VEC）以及用HRG-β2全长cDNA反义方向转染的衍生物（231/ASPOOL、231/AS31）中α(v)β(3)的水平。有趣的是，这与MDA MB 231细胞中活力以及细胞周期S期和G2/M期亚群因U0126而显著降低有关。此外，用LY294002特异性抑制PI-3'K通路也会诱导α(v)β(3)水平升高，但程度较小。此外，用U0126预处理MDA-MB-231细胞可拮抗小分子肽模拟物α(v)β(3)拮抗剂的作用。值得注意的是，抑制PI-3'K/AKT通路并未产生相同的效果，因此表明在MDA MB 231乳腺癌细胞中，“由外向内”以及“由内向外”的α(v)β(3)介导的信号传导主要通过ERK1/ERK2 MAPK通路进行。总体而言，这些结果有力地表明存在一种双向分子连接α(v)β(3)-ERK1/ERK2 MAPK，它将调节乳腺癌细胞的存活和增殖。
