Departamento de Biología de Sistemas, Universidad de Alcalá, Madrid, Spain.
Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain.
J Cell Physiol. 2019 May;234(5):7548-7559. doi: 10.1002/jcp.27515. Epub 2018 Oct 26.
Cyclooxygenase (COX)-derived prostaglandin E2 (PGE ) affects many mechanisms that have been shown to play roles in carcinogenesis. Recently, we found that, in androgen-independent prostate cancer PC3 cells, PGE acts through an intracrine mechanism by which its uptake by the prostaglandin transporter (PGT) results in increased intracellular PGE (iPGE ), leading to enhanced cell proliferation, migration, invasion, angiogenesis, and loss of cell adhesion to collagen I. These iPGE -mediated effects were dependent on hypoxia-inducible factor 1-α (HIF-1α), whose expression increased upon epidermal growth factor receptor (EGFR) transactivation by a subset of intracellular PGE receptors. Here, we aimed to study the role of COX in PGE protumoral effects in PC3 cells and found that the effects were prevented by inhibition of COX-2, which highlights its crucial role amplifying the levels of iPGE . Treatment with exogenous PGE determined a transcriptional increase in COX-2 expression, which was abolished by genetic or pharmacologic inhibition of PGT. PGE -induced increase in COX-2 expression and, thereby, in transcriptional increase in HIF-1α expression was due to EGFR activation, leading to the activation of Phosphoinositide 3-kinase/Akt, Extracellular signal -regulated kinases 1/2, p38 and Mitogen- and stress-activated protein kinase-1 (PI3K/Akt, Erk1/2, p38 and MSK-1). Collectively, the data suggest that EGFR-dependent COX-2 upregulation by a novel positive feedback loop triggered by iPGE underlies the intracrine pro-tumoral effects of PGE in PC3 cells. Therefore, this feedback loop may be relevant in prostate cancer for the maintenance of PGE -dependent cancer cell growth through amplifying the activity of the COX-2 pathway.
环氧化酶（COX）衍生的前列腺素 E2（PGE）影响许多已被证明在致癌作用中发挥作用的机制。最近，我们发现，在雄激素非依赖性前列腺癌细胞 PC3 中，PGE 通过一种胞内机制发挥作用，其通过前列腺素转运蛋白（PGT）摄取导致细胞内 PGE（iPGE）增加，从而增强细胞增殖、迁移、侵袭、血管生成和细胞对 I 型胶原的黏附丧失。这些 iPGE 介导的作用依赖于缺氧诱导因子 1-α（HIF-1α），其表达在细胞内 PGE 受体的一部分通过表皮生长因子受体（EGFR）的反式激活而增加。在这里，我们旨在研究 COX 在 PC3 细胞中 PGE 促肿瘤作用中的作用，发现 COX-2 的抑制可预防这些作用，这突出了其放大 iPGE 水平的关键作用。外源性 PGE 的处理确定了 COX-2 表达的转录增加，这被 PGT 的遗传或药理学抑制所消除。PGE 诱导的 COX-2 表达增加，从而导致 HIF-1α 表达的转录增加，这归因于 EGFR 的激活，导致磷酸肌醇 3-激酶/ Akt、细胞外信号调节激酶 1/2、p38 和丝裂原和应激激活蛋白激酶-1（PI3K/Akt、Erk1/2、p38 和 MSK-1）的激活。总之，数据表明，在 iPGE 触发的新型正反馈环下，EGFR 依赖性 COX-2 上调是 PC3 细胞中 PGE 胞内促肿瘤作用的基础。因此，这种反馈环可能与前列腺癌有关，通过放大 COX-2 途径的活性来维持依赖 PGE 的癌细胞生长。
