Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines
Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines
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DOI：
10.1677/jme.1.02155
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Baldi, Elisabetta
中科院分区：
文献类型：
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作者：
Bonaccorsi, Lorella;Nosi, Danielle;Baldi, Elisabetta
虽然雄激素和雄激素受体（AR）参与前列腺癌（PC）的肿瘤发生在初始阶段，不太清楚的是在先进的雄激素非依赖性（AI）阶段的疾病所发挥的作用。最近的几份报告表明，AR在PC衍生细胞系中的再表达决定了细胞的侵袭性较低的表型。我们先前已经证明，AR的再表达通过影响表皮生长因子受体（EGFR）的信号传导和内化过程来降低体外PC 3细胞的侵袭能力。在这里，我们表明，减少EGFR内化也是AR阳性PC细胞系LNCaP和22 Rv 1的一个特征。在PC 3-AR细胞中减少的内化与EGFR和介导内吞过程的两种衔接蛋白Grb 2和c-Cb 1之间的相互作用缺陷相关。由于这种减少的相互作用，主要由c-Cb 1介导的受体的泛素化也被改变。此外，我们表明，内化EGFR共定位与早期内体抗原-1，网格蛋白介导的内吞作用的标志物，在PC 3-Neo细胞，但不是在AR阳性细胞系。相反，EGFR在EGF刺激后在PC 3-AR细胞中保持与小窝蛋白-1的共定位。这些数据表明，AR的表达影响网格蛋白介导的EGFR内吞途径，根据最近的研究结果，这在受体信号传导的完整性中起着至关重要的作用。总之，这些数据强调了AR在PC细胞中EGFR内吞运输和活性信号传导调节中的作用。鉴于EGFR信号在癌细胞侵袭中的作用，我们的数据可以解释AR阳性细胞系中观察到的较低侵袭表型。
Although androgens and the androgen receptor (AR) are involved in tumorigenesis of prostate cancer (PC) in initial phases, less clear is the role played in advanced androgen-independent (AI) stages of the disease. Several recent reports indicated that re-expression of AR in PC-derived cell lines determines a less aggressive phenotype of the cells. We have previously demonstrated that re-expression of AR decreases the invasion ability of PC3 cells in vitro by affecting signalling and internalization processes of epidermal growth factor receptor (EGFR). Here, we show that reduced EGFR internalization is also a characteristic of AR positive PC cell lines LNCaP and 22Rv1. Reduced internalization in PC3-AR cells is associated to a defective interaction between the EGFR and two adaptor proteins which mediate the endocytotic process, Grb2 and c-Cb1. As a consequence of such reduced interaction, ubiquitination of the receptor, which is mainly mediated by c-Cb1, is also altered. In addition, we show that internalized EGFR co-localizes with early endosome antigen-1, a marker of clathrin-mediated endocytosis, in PC3-Neo cells but not in AR positive cell lines. Conversely, EGFR maintains co-localization with caveolin-1 after EGF stimulation in PC3-AR cells. These data suggest that expression of AR affects clathrin-mediated endocytosis pathway of EGFR, which, according to recent findings, plays an essential role in the completeness of signalling of the receptor. Taken together, these data emphasize the role of AR in the regulation of EGFR endocytotic trafficking and active signalling in PC cells. In view of the role of EGFR signalling in invasion of carcinoma cells, our data may explain the lower invasive phenotype observed in AR-positive cell lines.