Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models.
Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models.
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DOI：
10.1038/onc.2011.396
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发表时间：
2012-04-19
期刊：
影响因子：
8
通讯作者：
Nees, M.
中科院分区：
文献类型：
--
作者：
Harma, V.;Knuuttila, M.;Virtanen, J.;Mirtti, T.;Kohonen, P.;Kovanen, P.;Happonen, A.;Kaewphan, S.;Ahonen, I.;Kallioniemi, O.;Grafstrom, R.;Lotjonen, J.;Nees, M.
关键词：
在三维（3-D）器官型培养中，正常前列腺和一些恶性前列腺癌（PrCa）细胞系经历腺泡分化并形成球体。由PC-3和PC-3M形成的Acini，在其他PrCa细胞系中也不太明显，自发地经历侵袭性转换，导致上皮结构和基底层的解体，形成侵过足。这证明了上皮可塑性的高度动态性，平衡了上皮向间质转化与亚稳态腺泡分化之间的关系。本研究评估了脂质代谢物在上皮成熟中的作用。PC-3细胞在脱水血清中完全不能形成腺泡结构。补加溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1P）可有效挽救腺泡形态发生，抑制侵袭。通过siRNA（小干扰RNA）或特异性LPAR1抑制剂Ki16425阻断LPA受体1 （LPAR1）的功能可促进侵袭，而沉默其他对LPA或S1P应答的g蛋白偶联受体主要导致生长停滞或无作用。g蛋白Gα12/13和Gαi通过刺激RhoA和Rho激酶ROCK1和2激活Rac1，被鉴定为LPA信号传导的关键介质，而抑制腺苷酸环化酶和cAMP积累可能是次要的。干扰这些通路会特异性地阻碍转化细胞的上皮极化。相反，在未转化的正常细胞中阻断相同的途径促进分化。我们得出结论，LPA和LPAR1在三维培养中有效促进上皮成熟并阻断PrCa细胞的侵袭。临床转录组数据分析证实，LPAR1在PrCa的一个子集中表达减少。我们的研究表明LPAR1和g - α12/13信号传导具有转移抑制功能，调节细胞运动和侵袭，抑制上皮成熟。
Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.
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