Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Unité Mixte de Recherche 7196, Paris, France.
FASEB J. 2011 Jul;25(7):2201-10. doi: 10.1096/fj.10-169540. Epub 2011 Mar 14.
The insulin-like growth factor 1 receptor (IGF-1R) is involved in transformation, survival, mitogenesis and differentiation. It is overexpressed in many tumors and a validated target for anticancer therapy. In cell-free systems, polypyrimidic peptide nucleic acids (PNAs) can form triplex-like structures with messenger RNAs and halt the ribosomal machinery during the translation elongation. A 17-mer PNA that formed a PNA(2):mRNA complex with a purine-rich sequence located in the coding region of IGF-1R mRNA induced the synthesis of a truncated IGF-1R in vitro. This PNA down-regulated expression of the receptor by 70-80% in prostate cancer cells without affecting insulin receptor expression that exhibits high homology with IGF-1R. Inhibition occurs at the translational level, since the IGF-1R mRNA level measured by quantitative RT-PCR was not affected by PNA treatment. In addition, IGF-1R knockdown by PNA led to an attenuation of phosphorylation of downstream signaling pathways, PI3K/AKT and MAPK, involved in survival and mitogenesis and also to a decrease in cell transformation. Of the steric blockers tested, which included phosphorodiamidate morpholino oligomers and locked nucleic acids, PNA was unique in its ability to form triplex structures with mRNA and to arrest translation elongation.
胰岛素样生长因子 1 受体（IGF-1R）参与转化、存活、有丝分裂和分化。它在许多肿瘤中过表达，是抗癌治疗的有效靶点。在无细胞体系中，多嘧啶肽核酸（PNA）可以与信使 RNA 形成三链体样结构，并在核糖体延伸过程中阻止核糖体机械。一种 17 个碱基的 PNA 与 IGF-1R mRNA 编码区富含嘌呤的序列形成 PNA（2）：mRNA 复合物，在体外诱导 IGF-1R 截短体的合成。这种 PNA 在不影响与 IGF-1R 具有高度同源性的胰岛素受体表达的情况下，使前列腺癌细胞中受体的表达下调 70-80%。抑制发生在翻译水平，因为通过定量 RT-PCR 测量的 IGF-1R mRNA 水平不受 PNA 处理的影响。此外，PNA 对 IGF-1R 的敲低导致参与存活和有丝分裂的下游信号通路 PI3K/AKT 和 MAPK 的磷酸化减弱，也导致细胞转化减少。在所测试的空间位阻阻断剂中，包括磷酰胺酯吗啉寡聚物和锁核酸，PNA 是唯一能够与 mRNA 形成三链体结构并阻止翻译延伸的。
