The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells.
The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells.
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DOI：
10.1038/bjc.2014.22
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发表时间：
2014-03-04
影响因子：
8.8
通讯作者：
Houslay, M. D.
中科院分区：
文献类型：
--
作者：
Henderson, D. J. P.;Byrne, A.;Dulla, K.;Jenster, G.;Hoffmann, R.;Baillie, G. S.;Houslay, M. D.
cAMP特异性磷酸二酯酶（PDEs）的PDE4家族亚型以细胞类型依赖的方式表达，并有助于支持细胞内cAMP信号区隔化的范式。在这里，我们确定了PDE4D7异构体在前列腺癌进展过程中的差异调控，并揭示了其在控制前列腺癌细胞增殖中的作用。采用qPCR方法对19株前列腺癌细胞和异种移植物的PDE4转录物进行定量分析。由于PDE4D7在雄激素敏感（AS）和雄激素不敏感（AI）样品中表达显著下调，我们进一步研究了PDE4D7的表达。采用Western blot分析、PDE活性测定、免疫荧光染色和cAMP响应FRET试验研究了PDE4D7在VCaP （AS）和PC3 （AI）细胞系中的亚质膜定位。利用显性阴性蛋白表达和siRNA敲低破坏这种定位模式表明，通过基于电阻抗的增殖试验评估，PDE4D7的作用与增殖信号传导相反。在这里，我们确定了前列腺癌进展过程中PDE4D7亚型的差异调控。PDE4D7在AS细胞中高表达，在AI细胞中明显下调。我们的发现强调了这种下调的重要性，即PDE4D7对cAMP降解系在质膜上的PDE活性起主要作用，PDE4D7从这个隔室位移导致前列腺癌细胞的增殖增加。然而，PDE4D7 mRNA的表达不受雄激素受体信号轴的直接调控，尽管它与雄激素应答基因PART1有重叠的基因组结构。PDE4D7定位于质膜，可抑制前列腺内异常的非甾体生长信号或AS转移。PDE4D7的表达在AS和AI细胞表型之间显著下调。这种表达的变化可能提供一种新的雄激素非依赖性生物标志物，对其活性或表达的操纵可能为前列腺癌复杂的分子病理提供治疗可能性和见解。
Isoforms of the PDE4 family of cAMP-specific phosphodiesterases (PDEs) are expressed in a cell type-dependent manner and contribute to underpinning the paradigm of intracellular cAMP signal compartmentalisation. Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression and uncover a role in controlling prostate cancer cell proliferation. PDE4 transcripts from 19 prostate cancer cell lines and xenografts were quantified by qPCR. PDE4D7 expression was further investigated because of its significant downregulation between androgen-sensitive (AS) and androgen-insensitive (AI) samples. Western blot analysis, PDE activity assay, immunofluorescent staining and cAMP responsive FRET assays were used to investigate the sub-plasma membrane localisation of a population of PDE4D7 in VCaP (AS) and PC3 (AI) cell lines. Disruption of this localisation pattern using dominant-negative protein expression and siRNA knockdown showed that PDE4D7 acts in opposition to proliferative signalling as assessed by electrical impedance-based proliferation assays. Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression. PDE4D7 is highly expressed in AS cells and starkly downregulated in AI samples. The significance of this downregulation is underscored by our finding that PDE4D7 contributes a major fraction of cAMP degrading PDE activity tethered at the plasma membrane and that displacement of PDE4D7 from this compartment leads to an increase in the proliferation of prostate cancer cells. PDE4D7 mRNA expression is not, however, directly regulated by the androgen receptor signalling axis despite an overlapping genomic structure with the androgen responsive gene PART1. PDE4D7, which locates to the plasma membrane, acts to supress aberrant non-steroidal growth signals within the prostate or AS metastasis. PDE4D7 expression is significantly downregulated between AS and AI cell phenotypes. This change in expression potentially provides a novel androgen-independent biomarker and manipulation of its activity or its expression may provide therapeutic possibilities and insights into contributory aspects of the complex molecular pathology of prostate cancer.
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影响因子：
3.9
作者：
Huston, E.;Houslay, T. M.;Houslay, M. D.
通讯作者：
Houslay, M. D.
影响因子：
2.9
作者：
Huai, Q;Colicelli, J;Ke, HM
通讯作者：
Ke, HM
影响因子：
3.8
作者：
Jespersen, Christina G.;Norgaard, Mette;Borre, Michael
通讯作者：
Borre, Michael
DOI：
10.1073/pnas.1218206110
发表时间：
2013-04-09
影响因子：
11.1
作者：
Lin, De-Chen;Xu, Liang;Koeffler, H. Philip
通讯作者：
Koeffler, H. Philip
影响因子：
4.8
作者：
Lynch, MJ;Baillie, GS;Houslay, MD
通讯作者：
Houslay, MD