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雌激素受体α通过刺激生存信号传导、MYC表达并改变葡萄糖敏感性,驱动PTEN缺陷型前列腺癌的增殖。

Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity.

作者信息

Takizawa Itsuhiro, Lawrence Mitchell G, Balanathan Preetika, Rebello Richard, Pearson Helen B, Garg Elika, Pedersen John, Pouliot Normand, Nadon Robert, Watt Matthew J, Taylor Renea A, Humbert Patrick, Topisirovic Ivan, Larsson Ola, Risbridger Gail P, Furic Luc

机构信息

Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

出版信息

Oncotarget. 2015 Jan 20;6(2):604-16. doi: 10.18632/oncotarget.2820.

Abstract

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

摘要

虽然高剂量雌激素与雄激素联合使用可通过激活雌激素受体α(ERα)引发前列腺癌(PCa),但ERα在已形成肿瘤内的PCa细胞中的作用在很大程度上尚不清楚。在此,我们表明在高级别人类PCa中ERα的表达增加。同样,在由MYC过表达或PTEN缺失驱动的侵袭性PCa小鼠模型中,ERα也升高。在PTEN缺陷小鼠的前列腺内,存在ERα表达的渐进模式:在良性腺体中低表达,在背叶、侧叶和腹叶内的肿瘤中中等表达,在前前列腺内的肿瘤中高表达。这种表达与增殖标志物Ki67显著相关。此外,在源自PTEN缺陷肿瘤的细胞中体外敲低ERα会导致增殖显著且持续下降。ERα的缺失还会降低PI3K和MAPK途径的活性,这两者都是非基因组ERα作用的下游靶点。最后,ERα敲低会降低MYC蛋白水平,并降低细胞增殖对葡萄糖剥夺的敏感性,这与葡萄糖转运蛋白GLUT1表达降低相关。总体而言,这些结果表明ERα协调增殖和代谢以促进PCa细胞的肿瘤生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc44/4359242/7c940855ad5a/oncotarget-06-604-g001.jpg

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