Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy.
Unit of Basic and Applied Biosciences, Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
J Cancer Res Clin Oncol. 2018 Sep;144(9):1685-1699. doi: 10.1007/s00432-018-2696-3. Epub 2018 Jun 29.
Prostate cancer (PCa) cell radioresistance causes the failure of radiation therapy (RT) in localized or locally advanced disease. The aberrant accumulation of c-Myc oncoprotein, known to promote PCa onset and progression, may be due to the control of gene transcription and/or MEK/ERK-regulated protein stabilization. Here, we investigated the role of MEK/ERK signaling in PCa.
LnCAP, 22Rv1, DU145, and PC3 PCa cell lines were used in in vitro and in vivo experiments. U0126, trametinib MEK/ERK inhibitors, and c-Myc shRNAs were used. Radiation was delivered using an x-6 MV photon linear accelerator. U0126 in vivo activity alone or in combination with irradiation was determined in murine xenografts.
Inhibition of MEK/ERK signaling down-regulated c-Myc protein in PCa cell lines to varying extents by affecting expression of RNA and protein, which in turn determined radiosensitization in in vitro and in vivo xenograft models of PCa cells. The crucial role played by c-Myc in the MEK/ERK pathways was demonstrated in 22Rv1 cells by the silencing of c-Myc by means of short hairpin mRNA, which yielded effects resembling the targeting of MEK/ERK signaling. The clinically approved compound trametinib used in vitro yielded the same effects as U0126 on growth and C-Myc expression. Notably, U0126 and trametinib induced a drastic down-regulation of BMX, which is known to prevent apoptosis in cancer cells.
The results of our study suggest that signal transduction-based therapy can, by disrupting the MEK/ERK/c-Myc axis, reduce human PCa radioresistance caused by increased c-Myc expression in vivo and in vitro and restores apoptosis signals.
前列腺癌（PCa）细胞的放射抵抗导致局部或局部晚期疾病的放射治疗（RT）失败。异常积累的 c-Myc 癌蛋白，已知可促进 PCa 的发生和进展，可能是由于基因转录的控制和/或 MEK/ERK 调节的蛋白稳定。在这里，我们研究了 MEK/ERK 信号在 PCa 中的作用。
在体外和体内实验中使用 LnCAP、22Rv1、DU145 和 PC3 PCa 细胞系。使用 U0126、trametinib MEK/ERK 抑制剂和 c-Myc shRNA。使用 x-6 MV 光子线性加速器进行放射治疗。单独使用 U0126 或与照射联合使用，在小鼠异种移植瘤中确定其活性。
抑制 MEK/ERK 信号通过影响 RNA 和蛋白质的表达，在体外和体内 PCa 细胞异种移植模型中，不同程度地下调了 PCa 细胞系中的 c-Myc 蛋白，从而导致放射增敏。通过短发夹 RNA 沉默 c-Myc 可在 22Rv1 细胞中证明 c-Myc 在 MEK/ERK 通路中的关键作用，其作用类似于 MEK/ERK 信号的靶向作用。体外使用的临床批准化合物 trametinib 与 U0126 一样对生长和 C-Myc 表达产生相同的效果。值得注意的是，U0126 和 trametinib 导致 BMX 的急剧下调，已知 BMX 可阻止癌细胞凋亡。
我们的研究结果表明，基于信号转导的治疗可以通过破坏 MEK/ERK/c-Myc 轴，减少体内和体外由 c-Myc 表达增加引起的人 PCa 放射抵抗，并恢复凋亡信号。
