Caromile Leslie Ann, Dortche Kristina, Rahman M Mamunur, Grant Christina L, Stoddard Christopher, Ferrer Fernando A, Shapiro Linda H
Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Sci Signal. 2017 Mar 14;10(470):eaag3326. doi: 10.1126/scisignal.aag3326.
Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the β integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/β integrin axis may occur in other tumors.
前列腺上皮细胞中前列腺特异性膜抗原（PSMA）丰度增加是晚期转移性前列腺癌（PCa）的一个标志，且与预后呈负相关。然而，PSMA在功能上促进PCa进展的直接证据仍然难以捉摸。我们通过将PSMA缺陷小鼠与转基因PCa（TRAMP）模型杂交，生成了携带PSMA阳性或PSMA阴性PCa的小鼠，从而能够直接评估在有或没有PSMA的情况下PCa的发生率和进展情况。与PSMA阳性肿瘤相比，PSMA阴性肿瘤更小、分级更低、凋亡更多，血管更少，这与PSMA公认的促血管生成功能一致。相对于PSMA阳性肿瘤，缺乏PSMA的肿瘤中1型胰岛素样生长因子受体（IGF-1R）的丰度不到一半，PI3K-AKT信号介导的生存途径活性较低，而MAPK-ERK1/2信号介导的增殖途径活性较高。在生化方面，PSMA与支架蛋白RACK1相互作用，破坏了β整合素与IGF-1R复合物之间向MAPK途径的信号传导，转而激活了AKT途径。在PCa细胞系中对PSMA丰度进行操作重现了这种信号通路转换。对已发表数据库的分析表明，在患者中IGF-1R丰度、细胞增殖和抗凋亡标志物的转录本表达与PSMA丰度呈正相关，这表明这种转换可能与人类PCa相关。我们的研究结果表明，前列腺肿瘤中PSMA的增加通过改变正常信号转导途径来促进PCa进展，并且通过IGF-1R/β整合素轴增强的信号传导可能在其他肿瘤中也会出现。
