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Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

机译:EGF和TGF-α对人前列腺癌细胞中EGF受体表达的复杂转录后调控

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The epidermal growth factor receptor (EGFR) plays an important role in the development and progression of prostate cancer and its overexpression is associated with decreased survival. With progression, prostate cancer cells switch from epidermal growth factor (EGF) to transforming growth factor α (TGF-α) synthesis, which contributes to autocrine growth and unrestrained proliferation. To define the molecular mechanisms involved in the regulation of EGFR expression by EGF and TGF-α we studied three human prostate cancer cell lines, androgen-responsive (LNCaP) and -unresponsive (DU145 and PC3). Here we show that TGF-α stabilized EGFR mRNA two- to threefold in all three cell lines, whilst EGF stabilized EGFR mRNA ∼ twofold in LNCaP and DU145 cells, but not in PC3 cells. Both ligands increased EGFR transcription in LNCaP and DU145 cells, with less effect in PC3 cells. In all three cell lines EGF reduced total EGFR protein levels more than TGF-α, but this was associated with a greater increase in de novo protein synthesis with EGF compared to TGF-α. Only EGF, however, shortened EGFR protein stability (half-life decreased from 5 h to 120 min), resulting in rapid disappearance of newly synthesized EGFR protein. Both ligands increased total LNCaP and DU145 cell numbers. These studies demonstrate that the EGF- and TGF-α-induced upregulation of EGFR mRNA and protein in human prostate cancer cell lines is complex and occurs at multiple, transcriptional and post-transcriptional levels. Taken together, these data provide novel insight into the molecular mechanisms by which TGF-α would preferentially maintain an autocrine loop in human prostate cancer cells. Furthermore, this work suggests that in human prostate cancer cells ligand-specific differential intracellular trafficking of the EGFR plays a major role in regulating its expression. © 1999 Cancer Research Campaign
机译:表皮生长因子受体(EGFR)在前列腺癌的发生和发展中起重要作用,其过表达与生存期降低有关。随着进展,前列腺癌细胞从表皮生长因子(EGF)转变为转化生长因子(TGF-α)合成,这有助于自分泌生长和不受抑制的增殖。为了定义EGF和TGF-α调控EGFR表达的分子机制,我们研究了三种人类前列腺癌细胞系,雄激素反应性(LNCaP)和反应性非反应性(DU145和PC3)。在这里,我们显示在所有三个细胞系中,TGF-α使EGFR mRNA稳定了2至3倍,而LNCaP和DU145细胞中EGF使EGFR mRNA稳定了约2倍,而PC3细胞则没有。两种配体均增加LNCaP和DU145细胞中的EGFR转录,而对PC3细胞的影响较小。在所有三种细胞系中,EGF降低的总EGFR蛋白水平均高于TGF-α,但与TGF-α相比,与EGF的从头蛋白合成增加更多有关。但是,只有EGF缩短了EGFR蛋白的稳定性(半衰期从5小时缩短至120分钟),导致新合成的EGFR蛋白迅速消失。两种配体均增加了总的LNCaP和DU145细胞数量。这些研究表明,人前列腺癌细胞系中EGF和TGF-α诱导的EGFR mRNA和蛋白的上调是复杂的,并且在多个,转录和转录后水平上发生。综上所述,这些数据为TGF-α优先维持人前列腺癌细胞自分泌环的分子机制提供了新颖的见解。此外,这项工作表明在人类前列腺癌细胞中,EGFR的配体特异性差异细胞内转运在调节其表达中起着重要作用。 ©1999癌症研究运动

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