Fernández-Martínez Ana Belén, Lucio-Cazaña Javier
Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain,
Cell Mol Life Sci. 2015 Sep;72(17):3355-73. doi: 10.1007/s00018-015-1891-5. Epub 2015 Apr 1.
Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1α, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2-induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1α signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1α. We found that iPGE2 increases HIF-1α expression through iEP2-dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR-HIF-1α in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1α play a role in PC.
前列腺素E2（PGE2）和缺氧诱导因子-1α（HIF-1α）影响许多与前列腺癌（PC）发病机制相关的机制。在LNCaP细胞和PC3细胞中，PGE2可上调HIF-1α，研究表明HIF-1α有助于去势抵抗性PC（PC的一种致命形式）的转移和化疗耐药，并促进PC细胞的迁移、侵袭、血管生成和化疗耐药。在PC3细胞中选择性阻断PGE2-EP2信号通路可导致癌细胞增殖和侵袭受到抑制。PGE2影响许多已被证明在致癌过程中起作用的机制，如增殖、凋亡、迁移、侵袭和血管生成。最近，我们在PC3细胞中发现，这些PGE2诱导的大多数癌症相关特征是由于细胞内PGE2（iPGE2）所致。在此，我们旨在利用涉及前列腺素摄取转运体和表皮生长因子受体（EGFR）的药理学抑制以及EP2受体和HIF-1α的药理学和基因调控的实验方法，研究PC3细胞中iPGE2-细胞内EP2（iEP2）-HIF-1α信号在与PC进展相关的多个事件中的作用。我们发现iPGE2通过iEP2依赖的EGFR反式激活增加HIF-1α表达，并且在用PGE2或EP2激动剂处理的细胞中，抑制iEP2-EGFR-HIF-1α轴中的任何一个均可防止PC3细胞在体外增殖、黏附、迁移、侵袭和血管生成增加。值得注意的是，PGE2在从PC3细胞分离的细胞核中诱导了EP2拮抗剂敏感的DNA合成，这表明它们具有功能性EP2受体。这些结果表明，涉及EGFR和HIF-1α的PGE2-EP2依赖性自分泌机制在PC中发挥作用。
