Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells
Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells
复制标题
DOI：
10.1016/j.cellsig.2013.03.019
复制
发表时间：
2013-07-01
影响因子：
4.8
通讯作者：
Colas, Begona
中科院分区：
文献类型：
--
作者：
Cariaga-Martinez, Ariel E.;Lopez-Ruiz, Pilar;Colas, Begona
AKT 亚型在前列腺癌中表达，其表达和定位与临床特征具有不同的关联。然而，AKT 亚型在前列腺癌细胞中的独特作用在很大程度上尚不清楚。在本研究中，我们证明了 AKT1 和 AKT2 在细胞生长和迁移中的不同作用。 AKT1 和 AKT2 的消除降低了雄激素非依赖性细胞系 PC-3 的增殖，尽管机制不同。 AKT1 消融诱导细胞粘附丧失和随后的细胞凋亡。 AKT2（但不是 AKT1）消融促进细胞周期停滞在 G0/G1，与细胞周期蛋白 D、CDK6 和 CDK2 的下调以及 p27 的上调和细胞质到细胞核的重新分布相关。 p27 蛋白水平的增加是由于更多的基因转录和蛋白质稳定性的增加。 p27 稳定性的增加是由 Skp2 离域和 p27 Thr187 磷酸化水平较低引起的。 AKT1 和 AKT2 消除分别抑制和刺激 PC-3 细胞迁移。 AKT 同工型特异性功能可能与其亚细胞定位相关。我们发现 AKT1 和 AKT2 主要分别位于细胞质和细胞核中。在雄激素敏感细胞系LNCaP中，AKT1或AKT2的消除引起细胞凋亡，但在雄激素非依赖性LNCaP亚系中，AKT1消除的效果较低。而 AKT2 消融后没有观察到任何变化。综上所述，我们的数据表明 AKT1 和 AKT2 在 PC-3 细胞增殖和迁移的调节中具有非冗余的作用。这些可以通过它们的亚细胞定位和/或下游效应器的特定调节来解释。此外，AKT 同工型对前列腺癌进展的贡献可能从雄激素敏感阶段转变为激素难治阶段。这些发现可能有助于设计新的靶向策略来抑制前列腺癌中的 AKT 亚型。 (c) 2013 Elsevier Inc. 保留所有权利。
AKT isoforms are expressed in prostate cancer and their expression and localization have different associations with clinical characteristics. However, the distinct roles of the AKT isoforms in prostate cancer cells are largely unknown. In the present study, we demonstrate distinct roles for AKT1 and AKT2 in cell growth and migration. Ablation of AKT1 and AKT2 decreased the proliferation of the androgen-independent cell line PC-3, although by different mechanisms. AKT1 ablation induced loss of cell adhesion and subsequent apoptosis. AKT2 (but not AKT1) ablation promoted cell cycle arrest at G0/G1, associated with downregulation of cyclin D, CDK6 and CDK2, and upregulation and cytoplasmic-to-nuclear redistribution of p27. The increase of p27 protein levels was due to more gene transcription and an increase in protein stability. The increased stability of p27 was induced by delocalisation of Skp2 and a lower level of p27 phosphorylation at Thr187. AKT1 and AKT2 ablation inhibited and stimulated PC-3 cell migration, respectively. An AKT isoform-specific function could be associated with its subcellular localization. We found that AKT1 and AKT2 were mainly localised in the cytoplasm and nucleus, respectively. In androgen-sensitive cell line LNCaP, the ablation of AKT1 or AKT2 caused apoptosis but in androgen-independent LNCaP sublines, the effect of AKT1 ablation was lower; whereas no changes were observed after AKT2 ablation. Taken together, our data show that AKT1 and AKT2 have non-redundant roles in the regulation of PC-3 cell proliferation and migration. These could be explained by their subcellular localization and/or the specific regulation of downstream effectors. Furthermore, contribution of AKT isoforms to the progression of prostate cancer may change from an androgen-sensitive to a hormone-refractory stage. These findings may help design new targeted strategies for inhibiting AKT isoforms in prostate cancer. (c) 2013 Elsevier Inc. All rights reserved.