Department of Experimental Tumor Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, Moscow, 115522, Russia.
Medical Genetics Laboratory, I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
Chem Biol Interact. 2020 Oct 1;330:109243. doi: 10.1016/j.cbi.2020.109243. Epub 2020 Aug 27.
mTOR inhibitors are considered today to be one of the most promising anticancer drugs. Here to study the mechanism of the acquired resistance of MCF-7 breast cancer cells to mTOR inhibitors two different models of the cell resistance were used: rapamycin-resistant MCF-7/Rap subline developed under long-term rapamycin treatment, and metformin-resistant MCF-7/M subline obtained by long-term metformin treatment. We have found that both resistant sublines were characterized by common features: increased expression of mTOR-interacting Raptor protein, increased phosphorylation of Akt, and activation of growth-related transcriptional factor AP-1. Cell response to mTOR inhibitors was partially restored under treatment with PI3K inhibitor wortmannin supporting the direct connection between Akt activation and poor cell response to therapeutic drugs. Transfection of mir-181c, one of the positive regulators of Akt and mTOR, led to an increase in the cell resistance to both mTOR inhibitors, rapamycin and metformin, which correlated with Raptor overexpression and activation of Akt/AP-1 signaling. In general, the effect of Raptor overexpression in the resistant cells, as well as the ability of mir-181c to modulate the Raptor expression, can open novel perspectives in the treatment of rapalogues-resistant cancers, based on the drugs design targeting mir-181c/Raptor axis.
mTOR 抑制剂目前被认为是最有前途的抗癌药物之一。在这里，我们研究了 MCF-7 乳腺癌细胞对 mTOR 抑制剂获得性耐药的机制，使用了两种不同的细胞耐药模型：长期雷帕霉素处理下产生的雷帕霉素耐药 MCF-7/Rap 亚系，以及长期二甲双胍处理下获得的二甲双胍耐药 MCF-7/M 亚系。我们发现这两种耐药亚系都具有共同的特征：mTOR 相互作用的 Raptor 蛋白表达增加，Akt 的磷酸化增加，以及与生长相关的转录因子 AP-1 的激活。用 PI3K 抑制剂wortmannin 处理后，细胞对 mTOR 抑制剂的反应部分恢复，这支持了 Akt 激活与治疗药物反应不良之间的直接联系。转染 Akt 和 mTOR 的正调控因子 mir-181c，导致细胞对 mTOR 抑制剂雷帕霉素和二甲双胍的耐药性增加，这与 Raptor 过表达和 Akt/AP-1 信号的激活相关。总的来说，在耐药细胞中 Raptor 过表达的作用，以及 mir-181c 调节 Raptor 表达的能力，可以为基于针对 mir-181c/Raptor 轴的药物设计的耐药性癌症治疗开辟新的视角。
