Up-regulation of Skp2 after prostate cancer cell adhesion to basement membranes results in BRCA2 degradation and cell proliferation (Retracted Article)
Up-regulation of Skp2 after prostate cancer cell adhesion to basement membranes results in BRCA2 degradation and cell proliferation (Retracted Article)
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DOI：
10.1074/jbc.m604636200
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发表时间：
2006-08-04
影响因子：
4.8
通讯作者：
Greco, Margherita
中科院分区：
文献类型：
--
作者：
Moro, Loredana;Arbini, Arnaldo A.;Greco, Margherita
癌细胞与基底膜（BM）的异常相互作用是一个基本的病理生理过程，其引发导致癌细胞侵袭和转移的一系列事件。在这份报告中，我们描述了我们的调查结果有关的正常（PNT 1A）和高转移性（PC-3）的前列腺细胞粘附到BM蛋白质上引发的事件。与PNT 1A不同，PC-3细胞强烈粘附于Matrigel BM基质以及分离的IV型胶原、层粘连蛋白和硫酸乙酰肝素蛋白聚糖串珠蛋白（BM的主要成分）。这种异常增加的癌细胞粘附导致持续的BRCA 2蛋白耗竭和剧烈的细胞增殖，这是由β 1整合素介导的磷脂酰肌醇3-激酶激活触发的级联反应，导致蛋白酶体中的BRCA 2降解。后一种效应是由磷脂酰肌醇3-激酶依赖性上调Skp 2（Skp 1-Cul 1-F-box蛋白泛素复合物的一个亚基）协调的，Skp 2通过免疫共沉淀试验证明与BRCA 2直接相关，决定其泛素化，并最终靶向其进行蛋白酶体降解。通过小干扰RNA抑制Skp 2表达防止BRCA 2耗竭并抑制对细胞增殖的营养作用。这些结果为BRCA 2作为癌细胞生长调节剂的作用提供了额外的证据，并阐明了当与BM相互作用时，其在癌细胞中下调的分子机制，这是转移生物学中的关键步骤。进一步了解这一分子途径可能证明有价值的设计新的治疗策略，旨在修改前列腺癌的自然史。
Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by beta(1) integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its downregulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma.