El-Ashmawy Nahla E, El-Zamarany Enas A, Khedr Naglaa F, Selim Hend M, Khedr Eman G
Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt.
Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt.
Toxicol Rep. 2021 Jul 21;8:1530-1537. doi: 10.1016/j.toxrep.2021.07.012. eCollection 2021.
Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.
前列腺素E2（PGE2）和β1整合素与乳腺癌相关，二者均可促进乳腺癌的进展和转移。蛋白激酶C（PKC）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK）在乳腺癌发展过程中发挥了重要作用。我们开展本研究以阐明抑制E-前列腺素受体1（EP1）/PKC/MEK/β1整合素信号通路在减轻乳腺癌进展方面的作用，并评估中间信号叉头框蛋白C2（FOXC2）、E2F转录因子1（E2F1）、核因子κB（NF-κB）和生存素的作用。用EP1激动剂17-PT-PGE2处理MCF7细胞24小时，然后检测β1整合素。对用17-PT-PGE2处理的MCF7细胞，分别添加EP1、MEK、PKC或NF-κB抑制剂，随后检测每种情况下β1整合素基因表达和细胞增殖情况。向MCF7细胞中添加17-PT-PGE2后，细胞增殖以及细胞周期从G1期向S期的转变均增强。此外，EP1受体激活增加了β1整合素表达。相反，抑制EP1受体可使细胞增殖、β1整合素表达及细胞向S期的转变减少，但凋亡期细胞数量增加。对MEK、PKC和NF-κB的选择性抑制均抑制了17-PT-PGE2介导的β1整合素表达及细胞增殖。此外，17-PT-PGE2可上调FOXC2、磷酸化NF-κB、E2F1和生存素水平，而MEK、PKC和NF-κB抑制剂可抑制这些水平。靶向PKC/MEK信号通路的生化介质可能对开发用于癌症治疗的新化学实体具有重要价值。
