National Institute of Health Dr. Ricardo Jorge, Department of Genetics, Lisbon, Portugal.
Toxicol In Vitro. 2010 Sep;24(6):1689-95. doi: 10.1016/j.tiv.2010.05.018. Epub 2010 Jun 1.
Microcystin-LR (MCLR) is a peptide produced by freshwater cyanobacteria that induces severe hepatotoxicity in humans and animals. MCLR is also a potent tumour promoter and it has been proposed that this activity is mediated by the inhibition of protein phosphatases PP1/PP2A, possibly through the activation of proto-oncogenes c-jun, c-fos and c-myc. However, the mechanisms underlying MCLR-induced tumour promotion are still largely unknown, particularly in non-liver cells. In previous studies we have demonstrated that micromolar concentrations of MCLR induce cytotoxic effects in the kidney Vero-E6 cell line. The purpose of the present work was to evaluate whether the exposure to subcytotoxic concentrations of MCLR was sufficient to induce the proliferation of Vero-E6 cells. Through BrdU incorporation assay we show that at nanomolar concentrations MCLR stimulates cell cycle progression in Vero-E6 kidney cell line. Moreover, the analysis of mitogen-activated protein kinases p38, JNK and ERK1/2 activity revealed that the proliferative effect of MCLR is associated with the activation of the pro-proliferative ERK1/2 pathway. These results emphasise the importance to confirm in vivo the impact of MCLR on tumour promotion at kidney level.
微囊藻毒素-LR（MCLR）是一种由淡水蓝藻产生的肽，会导致人类和动物的严重肝毒性。MCLR 也是一种有效的肿瘤促进剂，有人提出这种活性是通过抑制蛋白磷酸酶 PP1/PP2A 来介导的，可能是通过激活原癌基因 c-jun、c-fos 和 c-myc。然而，MCLR 诱导肿瘤促进的机制在很大程度上仍然未知，特别是在非肝细胞中。在之前的研究中，我们已经证明了毫摩尔浓度的 MCLR 会在肾 Vero-E6 细胞系中引起细胞毒性作用。本研究的目的是评估亚细胞毒性浓度的 MCLR 是否足以诱导 Vero-E6 细胞的增殖。通过 BrdU 掺入试验，我们发现 MCLR 在纳摩尔浓度下刺激 Vero-E6 肾细胞系的细胞周期进程。此外，对有丝分裂原激活的蛋白激酶 p38、JNK 和 ERK1/2 活性的分析表明，MCLR 的增殖作用与促有丝分裂的 ERK1/2 途径的激活有关。这些结果强调了在体内确认 MCLR 对肾脏水平肿瘤促进作用的重要性。
